Marketing Authorization
Holders (MAHs)
Guidelines on Pharmacovigilance for Medicinal
Products for Human Use
Egyptian Guideline
On Pharmacovigilance
for Medicinal Products for Human Use
-Guideline for Marketing Authorization HoldersVersion 01 /January 2012
January 2012
January 2012
Table of contents
Table of contents............................................................................................................................................ 3
Introduction ................................................................................................................................................. 12
1. Legal Basis and Framework for Pharmacovigilance .......................................................................... 12
2. Roles & Responsibilities of Various Parties ......................................................................................... 12
2.1.
EPVC ................................................................................................................................................ 12
2.2.
2.3.
PART I ......................................................................................................................................................... 14
Guidelines for Marketing Authorization Holders .................................................................................... 14
1. Requirements for Qualified Person for Pharmacovigilance (QPPV) ................................................ 15
1.1.
1.2.
1.3.
Qualifications of a Qualified Person for Pharmacovigilance and Local Safety Responsible ........... 17
1.4.
1.4.1.
1.4.2.
1.4.3.
1.4.4.
1.4.5.
1.4.6.
1.5.
1.6.
1.7.
2.1.1.
2.1.2.
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2.1.2.a. Statement of the MAH and the qualified person regarding their availability and the means for the
notification of adverse reactions .................................................................................................... 27
2.1.2.b. Qualified Person Responsible for Pharmacovigilance ................................................................... 27
2.1.2.c. Organization................................................................................................................................... 28
2.1.2.d. Documented Procedures in place, which are documented in writing ............................................ 28
2.1.2.e. Databases ....................................................................................................................................... 31
2.1.2.f.
2.1.2.g. Training.......................................................................................................................................... 32
2.1.2.h. Documentation ............................................................................................................................... 32
2.1.2.i.
2.1.2.j.
2.1.3.
2.1.3.a. Statement of the MAH and the qualified person/LSR regarding their availability and the means for
the notification of adverse reactions .............................................................................................. 33
2.1.3.b. QPPV/LSR located in Egypt .......................................................................................................... 33
2.1.3.c. Organization................................................................................................................................... 34
2.1.3.d. Documented Procedures in place, which are documented in writing ............................................ 35
2.1.3.e. Databases ....................................................................................................................................... 37
2.1.3.f.
2.1.3.g. Training.......................................................................................................................................... 37
2.1.3.h. Documentation ............................................................................................................................... 38
2.1.3.i.
2.1.3.j.
2.2.
2.2.1.
QPPV........................................................................................................................................... 39
2.2.2.
2.2.3.
2.2.4.
2.2.5.
2.2.6.
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2.2.7.
2.2.8.
2.2.9.
2.2.10.
2.3.
2.3.1.
2.3.2.
2.3.3.
2.3.4.
2.3.5.
2.3.6.
2.3.7.
2.3.8.
2.3.9.
2.3.10.
2.3.11.
2.3.12.
2.3.13.
2.4.
Introduction ...................................................................................................................................... 47
3.2.
3.3.
3.4.
3.5.
3.6.
3.6.1.
3.6.2.
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Summary ..................................................................................................................................... 56
Pharmacovigilance Plan ................................................................................................................... 57
3.7.1.
Routine Pharmacovigilance......................................................................................................... 57
3.7.2.
3.7.3.
3.8.
3.8.1.
3.9.
3.10.
3.10.1.
3.11.
3.12.
3.12.1.
3.13.
3.14.
3.15.
3.15.1.
3.15.2.
3.15.3.
3.16.
Introduction ...................................................................................................................................... 72
4.2.
Requirements for Expedited Reporting of Individual Case Safety Reports (ICSRs) ....................... 73
4.2.1.
4.2.2.
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4.2.3.
4.2.4.
4.3.
4.3.1.
Reporting in the Period between the Submission of the Marketing Authorization Application and
the Granting of the Marketing Authorization .............................................................................. 82
4.3.2.
4.3.3.
4.3.4.
4.3.5.
4.3.6.
4.3.7.
4.3.8.
4.3.9.
4.3.10.
4.3.11.
Introduction ...................................................................................................................................... 87
5.2.
5.2.1.
5.2.2.
One Periodic Safety Update Report for Products Containing an Active Substance Authorized to
One MAH .................................................................................................................................... 88
5.2.3.
5.2.4.
5.2.4.a. Regular and Ad Hoc Submission of Periodic Safety Update Reports ........................................... 90
5.2.4.b. Submission of Periodic Safety Update Reports for Renewal of Marketing Authorizations .......... 91
5.2.4.c. Circumstances Where the Periodicity May Be Amended .............................................................. 92
5.2.4.d. Preparation of Periodic Safety Update Report according to the International Birth Dates............ 93
5.2.5.
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5.2.6.
5.3.1.
5.3.2.
5.3.3.
5.3.4.
5.3.5.
5.3.6.
5.3.7.
5.3.8.
5.3.9.
5.3.11.
5.4.
5.5.
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5.6.
6.2.
6.3.
6.4.
6.4.1.
6.4.2.
6.4.3.
6.5.
6.6.
6.7.
6.8.
7.2.
7.3.
7.3.1.
7.3.2.
7.3.3.
7.4.
7.5.
7.6.
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1.1.
1.2.
1.3.
1.4.
Situations Where a Direct Healthcare Professional Communication Should Be Considered ........ 135
1.5.
Key Principles for Preparation of Texts for Direct Healthcare Professional Communications ..... 136
1.6.
1.6.1.
1.6.2.
1.6.3.
1.2.
2. Abbreviations........................................................................................................................................ 149
3. Other Guidelines and Relevant Terminology .................................................................................... 151
3.1.
3.1.1.
Note for Guidance on the Electronic Data Interchange (EDI) of Individual Case Safety Reports
(ICSRs) and Medicinal Product Reports (MPRs) in Pharmacovigilance During the Pre- and PostAuthorization Phase in the European Economic Area (EEA) ................................................... 151
3.1.2.
Guideline on the Exposure to Medicinal Products During Pregnancy: Need for PostAuthorization Data .................................................................................................................... 151
3.1.3.
3.2.
3.2.1.
3.2.2.
Standard Terms on Pharmaceutical Dosage Forms, Routes of Administration and Containers 151
3.2.3.
3.2.4.
ICH-E2B(M) - Maintenance of the Clinical Safety Data Management Including: Data Elements for
Transmission of Individual Case Safety Reports ........................................................................... 152
4.1.1. ICH- E2B Q&As (R5): Questions and Answers Data Elements for Transmission of Individual Case
Safety Reports ........................................................................................................................... 152
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4.2.
ICH-E2C(R1): Clinical Safety Data Management Periodic Safety Update Reports for Marketed
Drugs including Addendum to ICH-E2C ....................................................................................... 152
4.3.
ICH-E2D: Post-Approval Safety Data Management - Definitions and Standards for Expedited
Reporting ........................................................................................................................................ 152
4.4.
4.5.
ICH-M1: Medical Terminology - Medical Dictionary for Regulatory Activities (MedDRA) ....... 152
4.6.
4.7.
ICH-M5: Data Elements and Standards for Drug Dictionaries ...................................................... 153
4.7.1.
4.7.2.
4.8.
Template for Egyptian Risk Management Plan (EG RMP) ................................................... 155
5.1.2.
5.1.3.
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Introduction
1. Legal Basis and Framework for Pharmacovigilance
Pharmacovigilance has been defined by the World Health Organization as the science and
activities relating to the detection, assessment, understanding and prevention of adverse effects or
any other medicine-related problem. The legal framework for Pharmacovigilance of
pharmaceutical products for human use in Egypt is given in the Ministerial Decree No. (397/1995)
concerning the establishment of National Pharmacovigilance Center, Ministerial Decree No.
(632/2010) concerning the establishment of Pharmacovigilance Committee and Assistant Minister
of Health decree No. (2/2010) concerning the regulations of Pharmacovigilance and
Pharmaceutical products safety. Being part of the Egyptian Drug Authority EPVC
recommendation and pharmacovigilance assessments are involved in the regulatory process of
other EDA departments, this considered as indirect legal framework.
The legislation listed above and this guideline describe the respective obligations of the MAH
(MAH) and of Egyptian Pharmacovigilance Center (EPVC) to set up a system for
Pharmacovigilance in order to collect, collate and evaluate information about suspected adverse
reactions. All relevant information should be shared between EPVC and the MAH, in order to
allow all parties involved in pharmacovigilance activities to assume their obligations and
responsibilities. This requires an intensive exchange of information between the MAH and EPVC
as well as procedures to avoid duplication, maintain confidentiality and ensure the quality of the
systems and data.
The requirements explained in these guidelines are based on the International Conference for
Harmonization (ICH) and the European Medicine Evaluation Agency (EMEA) guidelines, where
these exist, but may be further specified or contain additional requests in line with the legislation
of EPVC. Pharmacovigilance activities come within the scope of the criteria of quality, safety and
efficacy, as new information is accumulated on the medicinal product under normal conditions of
use in the marketing situation. Pharmacovigilance obligations apply to all authorized medicinal
products in Egypt.
This guidance is required to include technical requirements for the electronic exchange of
pharmacovigilance information in accordance with internationally agreed formats.
January 2012
EPVC continually monitors the safety profile of the products available in Egypt and takes
appropriate action where necessary and monitors the compliance of MAHs with their obligations
with respect to pharmacovigilance. EPVC should ensure that MAHs implement, when appropriate,
Risk Management Plans to effectively monitor and manage risks associated with the safety of their
products.
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PART I
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The appointment of the QPPV (and LSR) should be documented in an appropriate way, for
example in a job description or written agreement. A signed QPPV (and LSR) statement is also
required as part of the companys detailed description of the pharmacovigilance system
(DDPS) in marketing authorization applications.
Back-up arrangements should be in place for when Egypts QPPV(and LSR) is unavailable,
such as another appropriately qualified individual who can assume the role and responsibilities
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of the QPPV(and LSR)in their absence (while the role itself cannot be distributed among a
number of personnel, tasks may be delegated to a variety of individuals).
It is acknowledged that small companies may not have sufficient resource available in-house to
address the requirements for a QPPV and appropriate back-up arrangements. Therefore, MAH
may transfer any or all pharmacovigilance tasks and functions, including the role of the QPPV,
to another person(s) or organization (outsourcing) (this outsourcing does not apply for LSR).
The ultimate responsibility for the fulfillment of pharmacovigilance requirements always
resides with the MAH, but a contract QPPV also assumes specific legal responsibilities. When
a contract QPPV is employed the following should be considered:
(i) The MAH is responsible for ensuring that there is a contract in place between the company
and the QPPV, which adequately describes the responsibilities of each party and the tasks
to be allocated to the QPPV, prior to the QPPV commencing work with the MAH. Details
of the contractual arrangements for pharmacovigilance activities have to be notified to
EPVC, for example within the DDPS that is included as part of a marketing authorization
application. The contract should be appropriately amended or updated when changes to
contractual arrangements occur.
(ii) The MAH, or persons(s) appointed by the MAH for this task, should assess the contract
QPPV (or back-up QPPV) in order to ensure that he/she is appropriately qualified, has
knowledge of the applicable regulatory requirements and has the ability to fulfill the tasks
that have been assigned to him/her by the MAH, for example adequate arrangements for
24-hour availability. This assessment should be documented.
(iii) The contract QPPV would be expected to perform an assessment of the MAHs
pharmacovigilance system.
(iv) The MAH should ensure that the contract QPPV has sufficient authority to instigate
changes to the MAHs pharmacovigilance system in order to promote, maintain and
improve compliance with regulatory requirements.
(v) The contract QPPV should implement appropriate quality assurance (QA) and quality
control (QC) procedures in relation to the tasks that they have agreed to undertake on
behalf of the MAH.
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Egypt has not submitted a DDPS, the MAH should provide EPVC with current 24-hour contact
details of their QPPV/LSR and details of the back-up arrangements.
If a MAH holds marketing authorizations but does not currently market any of these medicinal
products, the company is still required to have an QPPV (and LSR) in place as pharmacovigilance
requirements, for example expedited reporting, Periodic Safety Update Report (PSUR) production
and literature searching, still apply. EPVC will maintain a list of QPPVs (and LSRs). This list will
include business address and contact details (including out of- business hours contact details).
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Establish and maintain the Market Authorization Holders (MAH) Pharmacovigilance System
(including all activities which contribute to the detection, assessment, understanding and
communication of safety information, as well as risk management activities). In addition, the
LSR is responsible with the QPPV for maintaining the MAH Pharmacovigilance System in
Egypt.
Oversee the safety profiles of the companys marketed products and any emerging safety
concerns.
Act as a single point of contact for the regulatory Authorities on a 24-hour basis, and provide
the contact point for pharmacovigilance inspections.
The QPPV/LSR is responsible for addressing specific requirements (as listed below). It is
recognized that this important role of the QPPV/LSR may impose extensive tasks on the
QPPV/LSR, depending on the size and complexity of the pharmacovigilance system and the
number and type of products for which the company holds authorizations. The QPPV/LSR may,
therefore, delegate specific tasks, under supervision, to appropriately qualified and trained
individuals (e.g. acting as safety experts for specific products), provided that the QPPV/LSR
maintains oversight of the system and an overview of the tasks that have been delegated (the
QPPV retains legal responsibility for compliance with these specific requirements).
In order to meet the requirements, it is essential that the MAH ensures that the QPPV/LSR has
sufficient authority to implement changes to the pharmacovigilance system in order to promote,
maintain and improve compliance. It is expected that the QPPV/LSR will receive adequate support
from senior management within the MAH to enable him/her to address his/her responsibilities and
to ensure that there are appropriate processes, resources, communication mechanisms and access to
all sources of relevant information in place for the fulfillment of the QPPVs/LSRs
responsibilities and tasks.
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database operations, contractual arrangements, compliance data (e.g. in relation to the quality,
completeness and timeliness for expedited reporting and submission of PSURs), audit reports and
training of personnel in relation to pharmacovigilance. Expectations with respect to QPPV/LSR
oversight are as follows:
(I) STANDARD OPERATING PROCEDURES
The QPPV/LSR should have an awareness of the MAHs procedures for key pharmacovigilance
activities. As appropriate, the QPPV/LSR may have input into or approve key written procedures
in order to assure compliance with the requirements. If the company has global and local written
procedures for key pharmacovigilance activities, the QPPV/LSR may need to have an awareness
of both types of procedure in order to ensure consistency and compliance across the organization.
(II) DATABASES
The QPPV/LSR should be aware of the system that is used to collect, evaluate and collate
information concerning all suspected adverse reactions. A computer database is often an essential
part of such a system. However, alternatives to a computer database may be acceptable provided
that the MAH is able to comply with the requirements to send electronic reports to EPVC. If a
computer database is used for collection and collation of adverse reaction information, the
QPPV/LSR should be aware of the validation status of the database, including any failures that
occurred during validation and the corrective actions that have been taken to address the failures.
The MAH should implement a procedure to ensure that the QPPV/LSR is able to obtain
information from the database at any time, for example to respond to requests for information
from EPVC. If this procedure requires the involvement of other personnel (e.g. information
technology (IT) programmers), then this should be taken into account in the arrangements made by
the MAH for supporting the QPPV/LSR outside of normal working hours. It may be appropriate
for the QPPV/LSR to be notified if significant changes to the pharmacovigilance database are
planned, such as being provided with the impact assessment report.
(III) QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES
The QPPV/LSR should have an awareness of the QC procedures that are used for key
pharmacovigilance activities, for example for case processing and PSUR production. These
procedures should be adequately documented. The MAH should implement a periodic QA audit
programme for pharmacovigilance of a type appropriate to the MAHs system. Audits should
cover all departments that may receive adverse reaction reports or that are involved in
pharmacovigilance activities (including drug safety, clinical research, product quality, medical
information, regulatory affairs, sales and marketing, the legal department) plus affiliate, contractor,
co-licensing and co-distribution companies, as appropriate. Audit and inspection report findings
relating to pharmacovigilance should be made available to appropriate MAH personnel, in
particular, the QPPV/LSR. The QPPV/LSR should also be made aware of the corrective actions
that are taken to address significant audit findings and compliance issues.
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The QPPV/LSR has specific legal responsibilities with respect to the preparation for EPVC of
serious adverse reaction reports, PSURs and Post-authorization Safety Study (PASS) reports; the
QPPV/LSR should receive compliance information on a periodic basis to enable him/her to assess
the quality, completeness and timeliness of submission of these reports.
(V) CONTRACTUAL ARRANGEMENTS
Where pharmacovigilance tasks have been transferred to another person or organization, detailed
and clearly documented contractual arrangements are required that adequately describe the
responsibilities of each party and the information to be exchanged between the parties. The
QPPV/LSR should have an awareness of those agreements that include pharmacovigilance tasks
and safety data exchange in order to ensure that the agreements facilitate compliance with EPVC
pharmacovigilance requirements. The MAH should implement mechanisms to facilitate this.
When a MAH intends to expand its product portfolio, for example by acquisition of another MAH
or by purchasing individual products from another MAH, it is advisable that the QPPV/LSR is
notified at an early stage of the due diligence process in order that the potential impact on the
pharmacovigilance system can be assessed. The QPPV/LSR may also have a role to play in
determining what pharmacovigilance data should be requested from the other MAH either pre- or
post-acquisition. In this situation, it is advisable for the QPPV/LSR to be made aware of the
sections of the contractual agreements that relate to responsibilities for pharmacovigilance
activities and safety data exchange.
(VI) TRAINING
The QPPV/LSR is expected to have received appropriate training in relation to the MAHs
pharmacovigilance system and this training should be documented. The QPPV/LSR should also
have an awareness of the system for, and type of, pharmacovigilance training provided to other
MAH personnel. MAH personnel should be made aware of the identity, contact details and
responsibilities of the QPPV/LSR, as appropriate. Ways in which a MAH can raise the profile of
the QPPV/LSR within an organization include posting details of the QPPV/LSR on the companys
intranet, highlighting the role of the QPPV/LSR in company newsletters or visits by the
QPPV/LAR to affiliate offices. The expectations listed above also apply to any person who
assumes the role of the QPPV/LSR, when the QPPV/LSR is unavailable.
1.4.2. Preparation of reports
The QPPV/LSR shall be responsible for the preparation for EPVC of Individual Case Safety
Reports (ICSR) for suspected serious adverse reaction and Periodic Safety Update Reports
(PSUR), in accordance with applicable legislative requirements and guidance.
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It should be stressed that LSR is not required personally to prepare the above reports (in case of
multinational MAHs where regional or headquarter QPPV may take on this responsibility).
However, the LSR should have an adequate and appropriate overview of the quality, completeness
and timeliness of adverse reaction reports and PSURs submitted to EPVC. The QPPV/LSR should
have sufficient authority to make changes to the pharmacovigilance system, where appropriate on
an international basis, to ensure compliance with reporting obligations.
Possible mechanisms by which the QPPV/LSR can obtain an overview of compliance include, but
are not limited to:
awareness and input into the processes and procedures established by the MAH for the
preparation and submission of adverse reaction reports and PSURs;
awareness and input into the training of key personnel involved in these activities;
periodic receipt and review of compliance data relating to preparation and submission of
adverse reaction reports and PSURs;
receipt and review of appropriate QC data and QA audit reports.
The QPPV (but not LSR) must prepare and sign the PSUR. The responsible QPPV may delegate
the preparation of the PSUR to an appropriately qualified and trained individual. That individual
may also sign the PSUR provided that there is a letter of delegation signed by the QPPV and
attached to the PSUR cover letter. Such a letter may cover more than one medicinal product and/or
more than one PSUR.
1.4.3. Answers requests from EPVC
The QPPV/ LSR shall be responsible for ensuring that any request from EPVC for the provision of
additional information necessary for the evaluation of the benefits and risks afforded by a
medicinal product is answered fully and promptly, including the provision of information about the
volume of sales or prescriptions of the medicinal product concerned.
A process should be established to ensure that requests to the MAH from EPVC for the
provision of information necessary for the evaluation of benefits and risks are promptly
communicated to the QPPV/LSR. This process should include affiliate offices, contractors, codistribution and co-marketing partners, as appropriate. Although the task of responding to
requests may be delegated to other personnel, the QPPV/LSR is legally responsible for the
completeness, accuracy and promptness of responses to requests from EPVC for information
necessary for the evaluation of benefits and risks.
Any other regulatory requests received and managed by regulatory affairs personnel, but it may
be related to the provision of information necessary for the evaluation of benefits and risks, the
QPPV/LSR should be made aware of this request and the response. The QPPV/LSR should
have awareness of the process for producing the response, should receive a copy of the
response and, where appropriate, should review and approve the response.
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The QPPV/LSR should have adequate and appropriate access to safety information, sales data
and product expertise to enable the QPPV/LSR to respond fully and promptly to requests for
information from EPVC.
The MAH/QPPV should consider implementing a system to capture and track requests for
information from Competent Authorities (Egyptian &/or global authorities), and the information
provided in response to such requests. The documentation associated with a Competent Authority
request and with the MAHs response to the request should be retained. The system implemented
may also be used to track specific Competent Authority requests for presentation and discussion of
data in PSURs.
1.4.4. Ongoing safety monitoring (post authorization)
The QPPV/LSR shall be responsible for the provision to EPVC- in a timely manner- of any safety
updates or any other information relevant to the evaluation of the benefits and risks afforded by his
medicinal product, including appropriate information on post-authorization safety studies,
literature safety information and worldwide regulatory actions due to safety reasons (e.g. label
changes, withdrawals, suspensions, recalls..etc.).
The QPPV/LSR should have oversight, either directly or through supervision, of the conduct of
continuous overall pharmacovigilance evaluation during the post-authorization period.
For this purpose, the QPPV/LSR should have an overview of the safety profiles and any emerging
safety concerns relating to the medicinal products for which the MAH holds authorizations in
Egypt. This does not mean that the QPPV/LSR has to be a product safety expert for all products,
but the QPPV/LSR is expected to have access to appropriate product-specific expertise when
required.
In addition to the mentioned above post-authorization safety monitoring activities, the QPPV of
the MAH for generic medicinal product, should continuously keep an eye on any safety updates
&/or safety regulatory actions taken for its reference medicinal product (whether this reference
product is authorized in Egypt or in the reference countries).
Some issues that the QPPV/LSR/MAH may want to consider in relation to these points are given
below.
(i) Mechanisms that have been implemented to keep the QPPV/LSR informed of emerging safety
concerns and any other information relating to the evaluation of the benefitsrisks balance.
This should include relevant literature information, relevant information from clinical trials
(e.g. recommendations from clinical trial safety-monitoring boards that may have implications
for the use of the product in authorized indications) and, where relevant to the evaluation of
benefits and risks, clinical trial Annual Safety Reports (ASRs) and study reports for products
authorized in Egypt.
(ii) Involvement of the QPPV/LSR in or awareness of safety committee meetings, where
applicable. If not, he/she should receive information or minutes from relevant meetings in
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order to be informed of emerging safety issues and the actions that have been taken to address
these issues.
(iii) Providing the same information on emerging safety concerns to the person who would act as a
back-up when the QPPV/LSR is absent.
(iv) The QPPV/LSR should be involved in the review of protocols for all Post-Authorization
Safety Studies (PASS) sponsored by the MAH (involving products authorized in Egypt), in
order to ensure compliance with pharmacovigilance requirements and this review should be
documented.
(v) When a PASS is conducted in Egypt, the QPPV/LSR is responsible for providing EPVC with
appropriate information relating to these studies. The QPPV/LSR should be made aware of
the status of the studies and be provided with copies of study reports (interim and final). The
QPPV/LSR should be made aware that protocols and reports had been submitted to EPVC to
ensure compliance with the legislation. The QPPV/LSR should be involved in decisions to
provide EPVC with new information relevant to the evaluation of the benefits and risks for
products authorized in Egypt. The QPPV/LSR should approve the submissions that are made.
The QPPV/LSR should be informed of the findings and have access to the reports from PASS
for products authorized in Egypt and sponsored by the MAH (within and outside Egypt). A
safety concern may unexpectedly be identified during a study on a medicinal product
authorized in Egypt but in a study or clinical trial that is not classified as a PASS. In this case,
the MAH and specifically the QPPV/LSR are expected to inform EPVC immediately and to
provide a brief report on progress at intervals and at study end as requested by EPVC. The
QPPV/LSR should be made aware of commitments made at the time of authorization
(including in Risk Management Plans (RMPs) for provision of additional information relevant
to the evaluation of the benefits and risks, and the QPPV/LSR should ensure that these
commitments are adequately addressed. The tasks may be delegated to other personnel, but
the QPPV/LSR should have an overview of how the commitments are addressed. The liaison
between EPVC and the MAH on pharmacovigilance-related issues should take place via the
QPPV/LSR.
1.4.5. Provide input into Risk Management Plans
The QPPV/LSR should have sufficient authority to provide input into Risk Management Plans
(RMPs) and into the preparation of regulatory action in response to emerging safety concerns, for
example variations, urgent safety restrictions and, as appropriate, communication to patients and
healthcare professionals (HCPs).
1.4.6. Contact point for pharmacovigilance inspections
The QPPV/LSR should also act as the MAHs contact point for pharmacovigilance inspections or
should be made aware by the MAH of any inspection that may impact the pharmacovigilance
system, in order to be available as necessary.
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MAH procedures should describe the communication process to be followed when an inspection
notification is received. The QPPV/LSR should be kept informed concerning the inspection
arrangements. The MAH should ensure that the QPPV/LSR is notified of inspection findings
relevant to his/ her role and responsibilities.
to provide input into Risk Management Plans (see Chapter I,3) and into the preparation of
regulatory action in response to emerging safety concerns (e.g. variations, urgent safety
restrictions, and, as appropriate, communication to Patients and Healthcare Professionals).
The MAH should assess risks with potential impact on the pharmacovigilance system and plan for
business contingency, including back-up procedures (e.g. in case of non-availability of personnel,
adverse reaction database failure, failure of other hardware or software with impact on electronic
reporting and data analysis).
January 2012
contracted person(s) or organization should implement quality assurance and quality control and
accept to be audited by or behalf of the MAH.
In cases of contractual arrangements between MAHs in relation to co-marketing of separately
authorized medicinal products which are identical in all aspects apart from their invented names,
these arrangements should include measures to avoid the duplicate submission of Individual Case
Safety Reports (e.g. literature reports) to EPVC.
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January 2012
26
January 2012
2.1.2.a.
Statement of the MAH and the qualified person regarding their availability and
the means for the notification of adverse reactions
The Applicant should provide a signed statement from the MAH and the QPPV to the effect that
the applicant has their services available as QPPV and has the necessary means for the collection
and notification of any adverse reaction occurring either in Egypt or other country. This statement
may make reference to the detailed description of the pharmacovigilance system and indicate what
is already in place, and confirm which items will be put in place before the product is placed on the
market /registered in Egypt.
2.1.2.b.
The name of the QPPV located in Egypt. The business address and contact details should be
provided in the Marketing Authorization Application form. Companies might, for example, use
a 24-hour telephone number through which the QPPV or their back-up can be reached,
diverting it to the appropriate person according to availability.
Summary Curriculum Vitae of the QPPV with the key information relevant to their role (main
qualifications, training and experience).
The QPPV training should include (but not limited to):
o Advanced pharmacovigilance
o MedDRA coding.
o Follow up, validation and assessment of the ICSRs
o Evidence based medicine, How to conduct literature search.
o Causality assessment
o Case Narrative Writing for Reporting Adverse Events
o Pharmacovigilance inspection
o Pharmaco-epidemiology
o Signal detection
o How to prepare a PSUR
o Risk Benefit assessment in Pharmacovigilance
o Pharmacovigilance Planning and Risk Management Plans
o How to prepare a DDPS
o Medical Aspects of Adverse Drug Reactions
In addition, QPPV should be aware of:
o European Pharmacovigilance regulations (as the Egyptian PV regulations are based on
the European PV regulations)
o Egyptian Pharmacovigilance regulation, PSUR, RMP, DDPS, Dear Dr Letter.
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January 2012
2.1.2.c.
Organization
Identification and location of the company units or other organizations where the principal and
global pharmacovigilance activities are undertaken in particular those sites where the main
databases are located, where Individual Case Safety Reports (ICSRs) are collated and reported
and where PSURs (Periodic Safety Update Reports) are prepared, reviewed (including where
medical review takes place) and processed for reporting to EPVC.
Flow diagrams indicating the flow of safety reports of different sources and types. These
should indicate how reports/information are processed and reported from the source, to the
point of receipt by EPVC, where appropriate, to healthcare providers.
A brief description of the responsibilities for quality assurance auditing of the companys
pharmacovigilance systems.
2.1.2.d.
The activities of the QPPV and the back-up procedure to apply in their absence;
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January 2012
The collection, processing (including data entry and data management), quality control, coding,
classification, medical review and reporting of ICSRs.
Reports of different types should be addressed:
o Organized data collection schemes (solicited), unsolicited, clinical trials, literature
o The process should ensure that reports from different sources are captured:
Egypt and other countries, healthcare professionals, sales and marketing personnel, other
MAH personnel, licensing partners,, compassionate use, patients, others;
The follow-up of reports for missing information and for information on the progress and
outcome of the case(s);
Training;
Archiving.
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January 2012
SOP
SOP title
number
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January 2012
A list and copies of the global and Egyptian procedures should be available within three days on
request by EPVC. Any additional local procedures should be available to respond to specific
requests.
All information received by the MAH should be managed in order to respect the confidentiality of
patients and reporters.
2.1.2.e.
Databases
A listing of the main databases used for pharmacovigilance purposes (e.g. compilation of safety
reports, expedited/electronic reporting, signal detection, sharing and accessing global safety
information) and brief functional descriptions of these should be provided including a statement
regarding the validation status of the database systems.
A statement should be included regarding the compliance of the systems with the internationally
agreed standards for electronic submission of adverse reaction reports.
A copy of the registration of the QPPV with the Egyptian Vigilance system and identification of
the process used for electronic reporting to EPVC.
There should be an indication of the responsibility for the operation of the databases and their
location (with reference to the locations identified under Section 1.2.c above organization).
2.1.2.f.
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January 2012
2.1.2.g.
Training
Staff should be appropriately trained for performing pharmacovigilance related activities. This
includes not only staff within the pharmacovigilance units but also staff who may receive or
process safety reports, such as sales personnel or clinical research staff. Provide a brief description
of the training system and indicate where the training records, Curricula Vitae (CVs) and job
descriptions are filed.
2.1.2.h.
Documentation
Provide a brief description of the locations of the different types of pharmacovigilance source
documents, including archiving arrangements. Reference can be made to the organization charts
provided under Section 3.2 above (organization).
2.1.2.i.
Provide a brief description of the quality management system, making cross-reference to the
elements provided under the above Sections. Particular emphasis should be placed on
organizational roles and responsibilities for the activities and documentation, quality control and
review, and for ensuring corrective and preventive action.
A brief description of the responsibilities for quality assurance auditing of the Pharmacovigilance
system, including auditing of sub-contractors, should be provided.
2.1.2.j.
Supporting Documentation
The MAH should ensure that the pharmacovigilance system is in place and documented.
An essential feature of a pharmacovigilance system is that it is clearly documented to ensure that
the system functions properly, that the roles and responsibilities and required tasks are clear to all
parties involved and that there is provision for proper control and, when needed, change of the
system.
Documentation supporting the pharmacovigilance system (and its detailed description) may be
required during the pre-authorization period, or post-authorization, for purposes such as
assessment or inspection.
Failure to submit these details in a marketing application
processing of the application. Inadequate details may provide
application. Pharmacovigilance inspectors will check
pharmacovigilance system with the DDPS submitted by the
variations) during pharmacovigilance inspections.
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January 2012
Statement of the MAH and the qualified person/LSR regarding their availability
and the means for the notification of adverse reactions
The Applicant should provide a signed statement from the MAH and the Egypt QPPV/LSR to the
effect that the applicant has their services available as Egypt QPPV/LSR and has the necessary
means for the collection and notification of any adverse reaction occurring in Egypt. This
statement may make reference to the detailed description of the pharmacovigilance system and
indicate what is already in place, and confirm which items will be put in place before the product is
placed on the market /registered in Egypt.
2.1.3.b.
The name of the Egypt QPPV/LSR located in Egypt. The business address and contact details
should be provided in the Marketing Authorization Application form. Companies might, for
example, use a 24-hour telephone number through which the Egypt QPPV/LSR or their backup can be reached, diverting it to the appropriate person according to availability.
Summary Curriculum Vitae of the Egypt QPPV/LSR with the key information relevant to their
role (main qualifications, training and experience).
The Egypt QPPV/LSRs training should include (but not limited to):
o Advanced pharmacovigilance
o MedDRA coding.
o Follow up, validation and assessment of the ICSRs
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January 2012
o
o
o
o
o
o
o
o
A description of the back-up procedure to apply in the absence of the Egypt QPPV/LSR.
The Curricula Vitae (CV) of the back-up person should be provided explaining his qualifications
and training. In addition it is recommended that a back-up person dedicated to pharmacovigilance
to be appointed in Egypt this will enable him to receive adequate & specialized pharmacovigilance
training to fulfill EPVC's requirements in the absence of Egypt QQPV/LSR. Note that both the
Egypt QPPV/LSR and the back-up person should be a physician or a pharmacist.
2.1.3.c.
Organization
Identification and location of the company units or other organizations where the principal and
global pharmacovigilance activities are undertaken in particular those sites where the main
databases are located, where Individual Case Safety Reports (ICSRs) are collated and reported
and where PSURs (Periodic Safety Update Reports) are prepared, reviewed including medical
review) (even if this occur outside Egypt) and processed for reporting to EPVC.
January 2012
product quality, quality assurance audit (for pharmacovigilance), and information technology
supporting pharmacovigilance database(s).Licensing partnerships are usually product-specific
and should be indicated in a product-specific addendum in the application for that product,
unless a partnership is a consistent feature of the companys organization across most products.
Flow diagrams indicating the flow of safety reports of different sources and types. These
should indicate how reports/information are processed and reported from the source, to the
point of receipt by EPVC, where appropriate, to healthcare providers.
It's understood that there is integration in the processing of the Egyptian ICSRs between
Egypt's office and MAH's headquarter. The flow chart should reflect this and clarify which of
the processing steps are carried out in Egypt's office & which are carried out in MAHs
headquarter.
A brief description of the responsibilities for quality assurance auditing of the companys
pharmacovigilance systems.
2.1.3.d.
The activities of the Egypt QPPV/LSR and the back-up procedure to apply in their absence;
The collection, processing (including data entry and data management), quality control, coding,
classification, medical review and reporting of ICSRs.
Reports of different types should be addressed:
o Organized data collection schemes (solicited), unsolicited, clinical trials, literature
o The process should ensure that reports from different sources are captured:
Egypt and other countries, healthcare professionals, sales and marketing personnel, other
MAH personnel, licensing partners,, compassionate use, patients, others;
The follow-up of reports for missing information and for information on the progress and
outcome of the case(s);
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January 2012
Training;
Archiving.
A complete list of the MAH pharmacovigilance related SOPs applied globally should be provided.
The objective/description of each SOP should be clarified with highlighting which of them are
applied in Egypt (ideally provided as the table below).
Description/ objective of SOP
SOP
number
SOP title
Applied in
Egypt
A list and copies of the Egyptian procedures should be available within three days on request by
EPVC. Any additional local procedures should be available to respond to specific requests.
All information received by the MAH should be managed in order to respect the confidentiality of
patients and reporters.
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January 2012
2.1.3.e.
Databases
A listing of the main databases used for pharmacovigilance purposes (e.g. compilation of safety
reports, expedited/electronic reporting, signal detection, sharing and accessing global safety
information) and brief functional descriptions of these should be provided including a statement
regarding the validation status of the database systems.
A statement should be included regarding the compliance of the systems with the internationally
agreed standards for electronic submission of adverse reaction reports.
There should be an indication of the responsibility for the operation of the databases and their
location (with reference to the locations identified under Section 1.2.c above organization).
It is understood that this global safety database might be located in the Headquarter however Egypt
QPPV/LSR must have online access to Egyptian safety cases and all Egyptian pharmacovigilance
data; otherwise at least backup database of the Egyptian data should always be kept in Egypt
office.
2.1.3.f.
Training
Staff should be appropriately trained for performing pharmacovigilance related activities. This
includes not only staff within the pharmacovigilance units but also staff who may receive or
process safety reports, such as sales personnel or clinical research staff. Provide a brief description
of the training system and indicate where the training records, Curricula Vitae (CVs) and job
descriptions are filed.
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January 2012
2.1.3.h.
Documentation
Provide a brief description of the locations of the different types of pharmacovigilance source
documents, including archiving arrangements. Reference can be made to the organization charts
provided under Section 3.2 above (organization).
2.1.3.i.
Provide a brief description of the quality management system, making cross-reference to the
elements provided under the above Sections. Particular emphasis should be placed on
organizational roles and responsibilities for the activities and documentation, quality control and
review, and for ensuring corrective and preventive action.
A brief description of the responsibilities for quality assurance auditing of the Pharmacovigilance
system, including auditing of sub-contractors, should be provided.
2.1.3.j.
Supporting Documentation
The MAH should ensure that the pharmacovigilance system is in place and documented.
An essential feature of a pharmacovigilance system is that it is clearly documented to ensure that
the system functions properly, that the roles and responsibilities and required tasks are clear to all
parties involved and that there is provision for proper control and, when needed, change of the
system.
Documentation supporting the pharmacovigilance system (and its detailed description) may be
required during the pre-authorization period, or post-authorization, for purposes such as
assessment or inspection.
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January 2012
2.2.1. QPPV
EPVC will maintain a list of QPPVs for MAHs within Egypt. This list will include business
address and contact details (including out of hours contact).
2.2.2. Availability of Pharmacovigilance Data
EPVC should monitor (e.g. by assessment of the detailed description of the pharmacovigilance
system and when inspections are carried out) that pharmacovigilance data are collated and
accessible by the MAH in Egypt.
2.2.3. Change in the Evaluation of the Risk-Benefit Balance of a Product
One of the key responsibilities of MAH is to immediately notify EPVC of any change in the
balance of risks and benefits of their products. Any failure to do so may pose a significant threat to
public health. Any evidence of failure to notify such changes will result in consideration of
enforcement action by EPVC/ The Central Administration of Pharmaceutical Affairs (CAPA).
2.2.4. Expedited Adverse Reaction Reporting
Requirements for expedited reporting of ICSRs are given in (Chapter I,4). Non-compliance with
expedited reporting may include complete failure to report, delayed reporting (i.e. submission
beyond 15 days) and submission of reports of poor quality (particularly where evidence suggests
that this results from inadequate company follow-up of individual cases). Failure to comply with
electronic reporting requirements will be monitored.
Methods available to EPVC for prospective monitoring of compliance with expedited reporting of
adverse reactions could be:
Monitoring adverse reaction reports received from MAHs against other sources to determine
complete failure to report.
Monitoring the time between receipt by MAH and submission to EPVC to detect late reporting.
Monitoring the quality of reports. Submission of reports judged to be of poor quality may
result in the follow-up procedures of MAH being scrutinized.
Monitoring that all adverse reactions that are kept in an electronic format are compatible with
EPVCs Pharmacovigilance data base.
Checking interim and final reports of post-authorization safety studies to ensure that all
qualifying serious reports have been submitted within 15 days.
At inspection there may be a review of a sample of reports on the MAH database to assess the
quality of data, determine whether the relevant reports have been expedited and are included on
39
January 2012
EPVCs Pharmacovigilance data base, and to confirm that procedures are in place to follow up
reports.
2.2.5. Periodic Safety Update Reports (PSURs)
PSURs are important pharmacovigilance documents. They provide an opportunity for MAHs to
review the safety profile of their products and ensure that the Summary of Product Characteristics
(SPC) and Package Leaflet are up to date. They also provide EPVC with a valuable source of
pharmacovigilance data. For these reasons EPVC place great importance on compliance with
periodic reporting. PSUR Non-compliance may include:
Incorrect format of the document: Report not in accordance with (Chapter I,5 PSUR).
Company core data sheet (CCDS) or SPC: Where changes have been made to the CCDS or
SPC since the submission of the last PSUR, the covering letter does not highlight the
differences between the CCDS and the SPC.
Previous requests from EPVC not addressed: Submission of a report where previous requests
from EPVC have not been addressed (e.g. close monitoring of specific safety issues).
PSURs do not contain all relevant individual case histories. The criteria used to select
individual case histories for inclusion in a particular PSUR should always be clear. It is often
simpler, and more transparent, to specify the criteria used to exclude cases from a particular
PSUR.
The summary tabulation for serious unlisted adverse reactions only contains data from the
period covered by the PSUR rather than cumulative data.
When a PSUR concludes that a products CCSI or SPC requires amending, no variation or
timetable for its submission is submitted along with the PSUR.
The meaningful differences between the RSI used to prepare the PSUR and the national SPC
for the product(s) are not described in the PSUR submission letter.
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January 2012
The conclusion of the PSUR does not adequately reflect the data presented within the PSUR.
For example, significant changes to the safety sections of the SPC are recommended
throughout the PSUR, but the conclusion section states that there were no significant issues
relating to changes in the riskbenefit profile of the product.
Compliance with the provisions of these measures will be monitored. These include:
and the specific obligations or follow-up measures as applicable to these. Normal marketing
authorizations may also include follow-up measures.
January 2012
Submission of data after the deadline agreed in the letter of undertaking from the company
(without previous agreement from EPVC);
January 2012
Triggers for the inspection are identified which do not relate to specific concerns about a
products safety or actual non-compliance, e.g.:
o The MAH has not previously been inspected;
o The MAH has placed their first product on the Egyptian market;
o The MAH has recently been or is involved in a merger or takeover process;
o The MAH has changed their system significantly (e.g. new database system, contracting
out of reporting activities).
Triggers for the inspection are identified which relate to specific concerns about a products
safety or actual non-compliance, e.g. significant issues relating to:
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January 2012
o Delays in carrying out or failure to carry out specific obligations or follow-up measures
relating to the monitoring of product safety, identified at the time of the marketing
authorization;
o Delays in expedited or periodic reporting;
o Incomplete reporting;
o Submission of poor quality or incomplete PSURs;
o Inconsistencies between reports and other information sources;
o Change in risk-benefit balance;
o Failure to communicate change in risk-benefit balance;
o Previous inspection experience;
o Information received from other authorities;
o Poor follow-up to requests for information from EPVC;
o Communication of information on pharmacovigilance concerns to the general public
without giving prior or simultaneous notification to EPVC;
o Product withdrawal with little or no advance notice to EPVC.
The above are examples and other issues may trigger a targeted pharmacovigilance inspection. The
presence of a trigger will not always lead to the conduct of an inspection.
2.3.4. Pharmacovigilance System Inspections
These inspections are designed to review the systems, personnel, facilities in place and their
compliance with pharmacovigilance obligations. They may use products as examples to test the
system. They may be routine or targeted.
2.3.5. Product-Specific Inspections
These inspections focus specifically on a given product and are usually targeted as a result of
triggers that have been identified (see Chapter I, 2.3.3).
2.3.6. Requesting and Reporting of Inspections
When necessary, inspection requests are prepared once adopted inspections are carried out by
EPVC.
2.3.7. Inspections of Contractors and Licensing Partners
Any party carrying out pharmacovigilance activities in whole or in part on behalf of, or in
conjunction with, the MAH may be inspected in order to confirm their capability to support the
MAHs compliance with pharmacovigilance obligations.
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January 2012
45
January 2012
public health impact of non-compliance but any instance of non-compliance may be referred for
enforcement action.
In addition, in the event of non-compliance, regulatory options include the following:
MAHs may be informed of non-compliance and advised on how this can be remedied.
Inspection
Non-compliant MAHs may be inspected to determine the extent of non-compliance and then
re-inspected to ensure compliance is achieved.
Warning
EPVC may issue a formal warning reminding MAHs of their pharmacovigilance regulatory
obligations.
EPVC will consider a policy of making public a list of MAHs found to be seriously or
persistently non-compliant.
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January 2012
47
January 2012
(ii) to make a plan with milestones indicating how safety knowledge will be extended postauthorization;
(iii) where necessary, to define the necessary measures to minimize known risks and monitor
the success of these measures.
The present Guideline provides guidance to Applicants and MAHs in Egypt on how to meet the
requirements for a detailed description of the risk management system (see Section 3.2 of this
chapter) and the circumstances when it is appropriate (see Sections 3.4 and 3.14 of this chapter) to
provide it. The risks addressed in this guidance are those related to non-clinical and clinical safety.
Where the disposal of the product might pose a particular risk because of remaining active
substance (e.g. patches) this should also be addressed. The Guideline is applicable to products in
both the pre-authorization and post-authorization phase.
For the purpose of this guidance, EPVC requires from the applicants/ MAHs to include the
following particulars and documents in the application for the authorization of medicinal
product for human use:
a) detailed description of the pharmacovigilance and, where appropriate, of the risk
management system which the applicant will introduce.
b) details of any conditions or restrictions which should be imposed on the supply or use of the
medicinal product concerned, including conditions under which the medicinal product may be
made available to the patients.
c) details of any recommended conditions or restrictions with regard to the safe and effective
use of the medicinal product.
d) for a period of five years following the initial placing on the market in Egypt, EPVC may
request that the MAH arrange for specific Pharmacovigilance data to be collected from
targeted groups of patients.
EPVC requires from MAH that a qualified person should be available to answer any inquiry on
their Pharmacovigilance program. This qualified person shall be responsible for the following:
1) ensuring that any request from EPVC for the provision of additional information necessary
for the evaluation of the benefits and risks afforded by a medicinal product is answered fully
and promptly, including the provision of information about the volume of sales or prescriptions
of the medicinal product concerned;
2) the provision to EPVC, of any other information relevant to the evaluation of the benefits and
risks afforded by a medicinal product, including appropriate information on post authorization
safety studies.
The detailed description of a risk management system should be provided in the form of an
Egyptian Risk Management Plan (EG-RMP) in the situations described in Chapter I.3, Section 4. It
is strongly recommended that discussions with EPVC on the need for, and content of, an EG-RMP
should take place in advance of submission. For the multinational MAH it is accepted to submit
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January 2012
Global/ European RMP annexed by the Egyptian Display of the RMP including the necessary
tailoring to Egypt when applicable.
A Safety Specification,
A Pharmacovigilance Plan; and
Part II:
An evaluation of the need for risk minimization activities; and if there is a need for
additional (i.e. non-routine) risk minimization activities
A risk minimization plan.
Part I of the EG-RMP incorporates the Safety Specification, which summarizes the safety profile
of the medicinal product at the particular point in time of its life-cycle, and the Pharmacovigilance
Plan which is based on the Safety Specification. Chapter I.3, section 6.2.g details the particular
EPVC requirements for the safety specification.
In Part II of the EG-RMP, on the basis of the Safety Specification, the Applicant/MAH should
consider carefully the need for risk minimization activities to be introduced. Risk minimization
activities may be routine or additional (see Chapter I.3, Section 8). Within the evaluation of
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January 2012
the need for risk minimization activities, the Applicant/MAH should discuss fully the use of
routine risk minimization activities and whether there is a need for additional risk minimization
activities. If only routine risk minimization activities are required there is no need to submit a risk
minimization plan. If additional risk minimization activities are thought necessary, the
Applicant/MAH should provide a risk minimization plan within Part II of the EG-RMP. This risk
minimization plan should contain both the routine and additional activities for each safety concern.
Every time the EG-RMP is updated (see Chapter I.3, Section 14) the Applicant/MAH should
reconsider its position vis--vis the need for risk minimization activities and Part II should be
updated accordingly.
on the initiative of an Applicant/MAH when they identify a safety concern with a medicinal
product at any stage of its life cycle.
In some circumstances, products which are not in the above categories which are seeking a new
authorization may require an EG-RMP:
Hybrid medicinal products where the changes compared with the reference medicinal product
suggest different risks
Bibliographical applications
For situations where the submission of an EG-RMP is not mandatory, the need for it should be
discussed with EPVC well in advance of the submission.
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January 2012
51
January 2012
The relevance of the findings to the use in humans should be discussed. If the product is intended
for use in special populations, consideration should be given to whether specific non-clinical data
needs exist.
3.6.2. Clinical Part of the Safety Specification
3.6.2.a.
Limitations of the safety database (e.g. related to the size of the study population, study
inclusion/exclusion criteria) should be considered, and the implications of such limitations with
respect to predicting the safety of the product in the marketplace should be explicitly discussed.
Particular reference should be made to populations likely to be exposed during the intended or
expected use of the product in medical practice.
In order to assess the limitation of the human safety database, the size of the study population
should be detailed using both numbers of patients and patient time (patient-years, patient-months)
exposed to the drug. This should be stratified, for relevant population categories such as age and
gender, type of study (e.g. randomized controlled trial, open clinical trial, observational study) and
any other relevant variable, such as dose, indication and duration of treatment. Limitations of the
database should also be presented in terms of the frequencies of adverse drug reactions detectable
given the size of the database. The limitations of the database should also be discussed with regard
to suspected long-term adverse reactions (e.g. malignancies) when it is unlikely that exposure data
is of sufficient duration and latency.
Post-marketing (non-study) exposure:
Where marketing of the medicine has occurred, the applicant / MAH should provide data on
patients exposed post-marketing. Exposure data based on the number of kilogrammes of medicinal
product sold divided by the average dose is only valid if the medicinal product is always taken at
one dose level for a fixed length of time which is not the situation with most medicinal products.
In paediatric populations or mixed populations of different indications or age groups, use of this
measure alone is inappropriate and other measures should be used.
A more accurate breakdown of drug exposure based on market research should be provided where
possible. When deciding which measure to use for exposure data, it is important to consider the
way a medicine is used. For example, for medicines used chronically, the appropriate measure may
be patient years of use. However, when use is typically limited and utilization is determined by
pack size (e.g. a course of antibiotics); a simple count of packs sold may be more appropriate. The
information should be stratified by relevant variables such as age, indication, dose and duration of
treatment.
3.6.2.b.
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January 2012
The Safety Specification should discuss which populations have not been studied or have only
been studied to a limited degree in the pre-authorization phase. The implications of this with
respect to predicting the safety of the product in the marketplace should be explicitly discussed.
Limitations of the database should also be presented in terms of the relevance of inclusion and
exclusion criteria in relation to the target population, in particular when exclusion criteria are not
proposed as contraindications for the drug. In discussing differences between target populations
and those exposed in clinical trials it should be noted that some differences may arise through trial
setting (e.g. hospital or general practice) rather than through explicit inclusion/exclusion criteria.
Populations to be considered for discussion should include (but might not be limited to):
Children;
The elderly;
Pregnant or lactating women;
Patients with relevant co-morbidity such as hepatic or renal disorders;
Patients with disease severity different from that studied in clinical trials;
Sub-populations carrying known and relevant genetic polymorphism;
Patients of different racial and/or ethnic origins.
This section should list the important identified and potential risks that require further
characterization or evaluation.
Identified risks that require further evaluation
More detailed information should be included on the most important identified adverse
events/adverse reactions, which would include those that are serious or frequent and that also
might have an impact on the balance of benefits and risks of the medicinal product. This
information should include evidence bearing on a causal relationship, severity, seriousness,
frequency, reversibility and at-risk groups, if available. Risk factors and potential mechanisms
should be discussed. These adverse events/adverse reactions should usually call for further
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January 2012
evaluation as part of the Pharmacovigilance Plan (e.g. frequency in normal conditions of use,
severity, outcome, at-risk groups).
Potential risks that require further evaluation
Important potential risks should be described in this section. The evidence that led to the
conclusion that there was a potential risk should be presented. It is anticipated that for any
important potential risk, there should be further evaluation to characterize the association.
Presentation of risk data
When the information is available, detailed risk data should be presented according to the
following format.
The frequency of important adverse reactions should be expressed taking into account the source
of the data. For a product already on the market, the reporting rate based on the number of
spontaneously reported adverse events/adverse reactions (in the numerator) and the sales data (in
the denominator) is very likely to underestimate the rate of occurrence of an adverse reaction in an
exposed population. When an accurate frequency is needed for an important adverse reaction, this
should always be based on systematic studies (e.g. clinical trials or epidemiological studies) in
which both the number of patients exposed to the medicinal product and the number of patients
who experienced the respective adverse event/adverse reaction are known.
The denominator should be expressed using the appropriate measure: e.g. number of patients or in
patient-time or equivalent units (courses of treatment, prescriptions, etc.) It should be stated clearly
which frequency parameter is being used: e.g. incidence proportion (patient units in the
denominator) or incidence rate (patient-time units in the denominator). Confidence intervals
should be provided. When using patient-time, the underlying assumption is that the hazard
function must be nearly constant over the follow-up time. Otherwise it should be split into relevant
categories where the assumption of constancy holds. Where appropriate, the period of major risk
should be identified. Adverse event/adverse reaction incidence rates should be presented for the
whole population and for relevant population categories.
For important identified risks, the excess and relative incidence should be given. Excess incidence
(in comparison to placebo and active comparator; if available) should be calculated based on the
best available evidence (e.g. meta-analytic techniques) for each population (total controlled, total
controlled plus open label extension, total study). Time to event data should be summarized using
survival techniques which take appropriate account of informative censoring. Cumulative hazard
functions may provide a simple visual comparison of the competing risks of different adverse
reactions. These data can be stratified by substance (to investigate the difference in the adverse
event profile between active and placebo), or by risk factors such as dose, gender or age.
The potential impact of the most important identified and important potential risks should be
addressed using for example: strength of evidence, supporting plausibility, nature of evidence and
potential public health burden, morbidity and case fatality. Recording this in a structured form will
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facilitate assessment of the potential significance of a safety concern. Classification of the safety
concern by dose, time and risk factors is encouraged. The identification of susceptible patients
should receive specific attention, possibly from analysis of cases. It is likely that the adverse
reactions will require further evaluation as part of the Pharmacovigilance Plan.
3.6.2.d.
Interactions
Identified and potential pharmacokinetic and pharmacodynamic interactions should be discussed.
For each, the evidence supporting the interaction and possible mechanism should be summarized,
and the potential health risks posed for the different indications and in the different populations
should be discussed.
It should be stated which interactions require further investigation.
3.6.2.e.
Epidemiology
The epidemiology of the indication(s) should be discussed. This discussion should include
incidence, prevalence, mortality and relevant co-morbidity, and should take into account whenever
possible stratification by age, sex, and racial and/or ethnic origin. Differences in the epidemiology
in the different regions should be discussed, where feasible.
In addition, for important adverse events that may require further investigation, it is useful to
review the incidence rate of these events among patients in whom the medicinal product is
indicated (i.e. the background incidence rates). Information on risk factors for an adverse event
would also be useful to include, if available. For example: if a medicinal product is intended for
treating prostate cancer the target population is likely to be men over the age of 50 years. This
population is also at increased risk of myocardial infarction. If it is suspected that the medicinal
product might also cause myocardial infarction, it would be useful to know how many cases would
be expected amongst prostate cancer patients (ideally) or men in the same age group, not on the
medicinal product.
3.6.2.f.
The Safety Specification should identify risks believed to be common to the pharmacological
class.
If a risk which is common to the pharmacological class is not thought to be a safety concern with
the medicinal product, this should be justified.
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3.6.2.g.
The Applicant/MAH is requested to discuss the topics below. If the potential is thought to be
significant, the topic should be identified as an important potential risk and means for reducing or
minimizing it discussed in the evaluation of the need for risk minimization activities. In this
context, significant means that there is a reasonable likelihood that it will occur. Where a
particular topic is not relevant to the individual medicinal product, this should be stated along with
the reason.
Potential for overdose
Special attention should be given in particular cases, e.g. where there is a narrow therapeutic
margin, a medicinal product with significant toxicity and/or there is an increased risk of overdose
in the target population.
Potential for transmission of infectious agents
The Applicant/MAH should discuss the potential for the transmission of an infectious agent in line
with Chapter I.4.
Potential for misuse for illegal purposes
The potential for misuse for illegal purposes should be considered. If appropriate, the means of
limiting this, e.g. by the use of colorants and/or flavorings in the dosage form, limited pack size
and controlled distribution should be discussed in the RMP section Evaluation of the Need for
Risk Minimization Activities.
Potential for off-label use
The potential for off-label use should be discussed. This is particularly relevant where a medicinal
product has an indication restricted to a subset of the population within a disease area or there are
situations where the medicinal product must not be given for safety reasons. The potential for use
in other disease areas should also be considered where this is likely.
Potential for off-label pediatric use
If the disease or disorder which is being treated or prevented is found in the pediatric population,
the potential for off-label pediatric use should be discussed.
3.6.3. Summary
At the end of the Safety Specification a summary should be provided of the:
Based on this summary the Applicant/MAH should provide a Pharmacovigilance Plan and an
evaluation of the need for risk minimization activities (see Template in Annex 5.1.1).
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For important identified and potential risks, objectives may be to measure the incidence rate in
a larger or a different population, to measure the rate ratio or rate difference in comparison to a
reference medicinal product, to examine how the risk varies with different doses and durations
of exposure, to identify risk factors or to assess a causal association.
For important missing information, the objective may simply be to investigate the possibility of
a risk or to provide reassurance about the absence of a risk.
The threshold for investigating a safety concern further will depend upon the indication, the target
population, and the likely impact on public health. For example, a safety concern with a vaccine
might have a lower threshold for investigation than the same issue in a medicine used in the
palliative treatment of metastatic cancer.
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The Table I.6.A (chapter I, 6) lists some of the epidemiological activities which might be
considered for inclusion in a Pharmacovigilance Plan. Additional Pharmacovigilance activities
included in the Pharmacovigilance Plan should be designed and conducted according to the
recommendations in the Guidelines for Good Pharmacoepidemiology Practices (GPP). For studies
involving children, the Guideline on Conduct of Pharmacovigilance for Medicines Used by the
Paediatric Population (see Annex 3.1.3) should be consulted. The responsibility for the scientific
value of study protocols remains with Applicants or MAHs, even if they have been previously
discussed with EPVC.
3.7.3. Action Plan for Safety Concerns
Within the Pharmacovigilance Plan the action plan for each safety concern should be presented
and justified according to the following structure (see also Annex 5.1.1):
Safety concern
Objective of proposed action(s)
Action(s) proposed
Rationale for proposed action(s)
Monitoring by the Applicant/MAH for safety concern and proposed action(s)
Milestones for evaluation and reporting.
Protocols (draft or otherwise) for any formal studies should be provided. Details of the monitoring
for the safety concern in a clinical trial could include: stopping rules, information on the drug
safety monitoring board and when interim analyses will be carried out.
Although not explicitly included in this structure, it is also necessary in the EG-RMP to explain the
decision making processes which will depend on the outcomes of the proposed actions. The
possible consequences of the study outcomes should be discussed.
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However, for some risks, routine risk minimization activities will not be sufficient and additional
risk minimization activities will be necessary. If these are required, they should be described in the
risk minimization plan (see Chapter I.3, Section 9) which should be included in Part II of the EGRMP.
Within the evaluation of the need for risk minimization activities, the Applicant/MAH should also
address the potential for medication errors (see Chapter I.3, Section 8.1) and state how this has
been reduced in the final design of the pharmaceutical form, product information and packaging.
As a rule, Applicants/MAHs should always consider the need for risk minimization activities
whenever the Safety Specification is updated in the light of new safety information on the
medicinal product. In some circumstances, it may be appropriate to suggest that an additional risk
minimization activity be stopped because experience with the medicinal product suggests that it is
no longer necessary for the safe and effective use.
3.8.1. Potential for Medication Errors
Applicants/MAHs are encouraged routinely to consider the likelihood of medication errors. In
particular, they should assess prior to marketing, common sources of medication errors.
During the development phase and during the design of the medicinal product for marketing, the
Applicant needs to take into account potential reasons for medication error including -but not
limited to- the following:
The naming, presentation (e.g. size, shape and coloring of the pharmaceutical form and
packaging), instructions for use (e.g. regarding reconstitution, parenteral routes of
administration, dose calculation) and labeling are among the items to be considered.
If a product has life-threatening potential when administered by an incorrect route,
consideration should be given as to how such administration can be avoided. This is
particularly important when it is common practice to administer the product at the same time as
other medicinal products given by the hazardous route.
The need for visual (or physical) differentiation between strengths of the same medicinal
product and between other medicinal products commonly administered or taken at the same
time should be discussed.
When a medicinal product is likely to be used by a visually impaired population, special
consideration should be given to the potential for medication error.
Consideration should be given to the prevention of accidental ingestion or other unintended use
by children.
Medication errors identified during product development should be discussed and information on
the errors, their potential cause(s) and possible remedies given. Where applicable an indication
should be given of how these have been taken into account in the final product design.
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If during the post-marketing period it becomes apparent that adverse reactions are occurring as a
result of medication errors, this topic should be discussed in the updated EG-RMP and ways of
limiting the errors proposed.
Safety concern
Objective of proposed action(s)
Action(s) proposed
Rationale for proposed action(s)
Monitoring by the Applicant/MAH for safety concern and proposed action(s)
Milestones for evaluation and reporting.
In addition, for each proposed additional risk minimization activity, a section should be included
detailing how the effectiveness of it as a measure to reduce risk will be assessed (see Annex 5.1.1).
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understanding of which activities are most appropriate in addressing specific types of safety
concerns.
3.12.1. Assessment of Risk Minimization
Direct measurement of risk minimization should be employed whenever feasible. Surrogate
measures should be considered when this is not feasible or to provide interim assessments whilst
awaiting direct risk minimization measurements. For example, for measures based on the provision
of information to professionals, descriptive studies or surveys which assess whether the
information is being effectively communicated might be appropriate. The use of medical databases
might also allow direct measures of how uniformly such advice was being adhered to by
reviewing, for example, concomitant medication or the results of laboratory tests. Since such
studies are likely to be required with increasing frequency, the availability of such databases will
be an ever more important factor in risk management. If the prescribing databases are further
linked to patient clinical outcome, a study of the adequacy of the prescribing process could be
designed to evolve over time into a full risk reduction study.
It is clear that, even when risks are of a type which can be directly measured, ethical and practical
considerations may prevent prospective comparison. It may be scientifically difficult to make
direct comparison between a situation with and without the intervention to be assessed and may
not be achievable in timescales which allow the lessons learned to be used to improve risk
management. In particular this will occur when risks associated with long-term exposure or very
rare events are to be reduced. For products where a risk minimization plan has been introduced
after some time on the market a comparison with historical data can be made. Notwithstanding the
above, Applicants/MAHs should investigate new methodologies for monitoring and assessment.
The relationship between activities and safety concerns may be clarified by a cross-tabulation of
the two categories showing which safety concerns are addressed by each activity (see Annex
5.1.1).
Summary of activities for each safety concern:
This should be a simple table, listing each safety concern and summarizing the activities (both
Pharmacovigilance and, where appropriate, risk minimization) which will be taken. Where
appropriate, it should provide a cross-reference to the actions in the Pharmacovigilance Plan and
the risk minimization activities for the individual safety concern.
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when it will be possible to assess with sufficient precision the effect of risk factors associated
with the occurrence of an adverse reaction;
when the results of ongoing or proposed safety studies are expected to be available;
the seriousness and magnitude of the risk for which risk minimization activities are being
proposed. Evaluation of the effectiveness of the activities will need to be carried out earlier and
more frequently if the risk is very serious.
January 2012
when new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimization activities;
within 60 days of an important (Pharmacovigilance or risk minimization) milestone being
reached or the results of a study becoming available;
at the request of EPVC.
A cover letter should be submitted with the updated EG-RMP briefly summarizing the changes
from the previous EG-RMP.
Where no changes to any part of the EG-RMP have occurred since the last submission, a letter
stating this, and the date of the last EG-RMP submission should be sent. In this circumstance it is
not necessary to re-submit the EG-RMP with the letter.
Periodic Safety Update Reports
A summary of any amendments made to the EG-RMP, prior to the data lock point of the Periodic
Safety Update Report (PSUR), should be included in the PSUR (see Addendum to ICH E2C
Clinical Safety Data Management, Periodic Safety Update Reports for Marketed Drugs, Section
2.8.3 (see Annex 4).
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Type of the
activity
Safety
Concern
PV (routine, additional)
Risk minimization
(routine, additional)
Highlight
differences if any
(even minor
difference)
Justification
a) If the MAH/Applicant proposes not to implement in Egypt any of the activities stated in the
Global/EU RMP; this should be clearly highlighted in the above table and comprehensive
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justification should be supplied, in addition explanation of how the safety concern intended by
this activity will then be managed in Egypt.
b) If the MAH/Applicant proposes some differences (even minor ones) in the action plan of
specific activity to be followed in Egypt other than those described in the Global/EU RMP; the
differences should be clearly highlighted in the table and comprehensive justification should be
supplied as well.
c) If the MAH/Applicant will implement in Egypt additional activities over those stated in the
Global/EU RMP (e.g. due to Egypt-specific/region-specific safety concern/s or due to other
justified reason); this should be presented in details according to the following structure (see
Annex 5.1.1 section 2.3 Detailed action plan for specific safety concerns), as appropriate any
relevant documents should be annexed. It is also important to realize that for activities already
exist in the Global/EU RMP but different action plan in Egypt is proposed by MAH/Applicant
this action plan cannot be included in this section as if it is plan for additional activity, instead
the difference should be described in the previous table.
Safety concern
<>
Action(s) proposed
<>
<>
<>
<>
<>
<>
RMPs tend to focus on what is already known rather than identifying the areas in which
information is lacking.
Information is poorly presented, with long and complicated tables. This does not facilitate the
assessment process.
The relevance of the epidemiology of the disease to the target indication is not sufficiently
considered. For example, the proposed new indication for a given drug is for a specific
complication of poorly controlled type 2 diabetes mellitus. Several pages of information are
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provided describing the epidemiology of type 2 diabetes, without any reference to the target
indication.
Justification is often not provided by the MAH when it is considered that extra measures are
not required in the risk-minimization section.
Promotional activities are not separated from risk-minimization activities; for example
educational materials are not necessarily risk minimization tools and should not be routinely
included in the RMP.
Plans for monitoring the success of risk-minimization activities are often lacking.
Discrepancies exist between the DDPS and the pharmacovigilance plan, because of a failure of
communication between the different groups within organizations responsible for writing the
different documents or sections within the documents.
The submitted Global/EU RMP is not annexed by the Egyptian Display of the RMP.
RMPs can be used to support existing pharmacovigilance activities to understand more fully the
safety profile of a product. In essence, the RMP is a means by which the MAH can assure itself,
Competent Authorities and the public of how the safety of the medicine will be specifically
monitored and the risk to public health minimized.
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The educational program may include but is not limited to the following materials:
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The choice of media may also need to be considered (written, audio or video) as well as the
use of drawing/symbols to improve understanding. For medicines where the target
population may include a larger proportion of visually impaired patients, the use of Braille or
audio media should be given special consideration. Pre-testing materials in the target
audience(s) is highly desirable to help ensure good comprehension and acceptance of the
communication method and contents.
A variety of testing methods such as readability testing, focus groups or surveys could be
used.
Specific training programs may be considered in certain circumstances. However, it is
unlikely that prescription/dispensing of the medicine can be limited to people who have
undertaken such a program.
The above educational materials should be in strict compliance with the contents of the SPC
and the Package Leaflet and must be agreed with EPVC.
2. Legal Status of a Medicine
It is possible that controlling the conditions under which a medicine may be made available
could reduce the risks associated with its use or misuse. This might be achieved by control of
either who may be permitted to prescribe or dispense a medicine or by controlling who, or
the conditions under which a patient, may receive a medicine.
When a marketing authorization is granted, it must include details of any conditions or
restrictions imposed on the supply or the use of the medicinal product, including the
conditions under which the medicinal product may be made available to Patients. This is
commonly referred to as the legal status of a medicinal product. Typically it includes
information on whether or not the medicinal product is subject to medical prescription. It
may also restrict where the medicine can be administered (e.g. to a hospital) or by whom it
can be prescribed (e.g. specialist).
Although the use of legal status is not an activity that can be used directly by an Applicant
for the purposes of risk reduction, the Applicant could request EPVC to consider a particular
legal status.
For medicines only available upon prescription, additional conditions may be imposed by
classifying medicines into those available only upon either a restricted medical prescription
or a special medical prescription. When considering classification as subject to restricted
medical prescription the following factors shall be taken into account:
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the medicinal product is intended for outpatients but its use may produce very
serious adverse reactions requiring prescription drawn up as required by a
specialist and special supervision throughout the treatment.
Although restriction to use in a hospital environment may in practice ensure that the
medicine is always prescribed by a specialist, this needs to be balanced against the
inconvenience to patients if they need to attend a hospital for every prescription. Care also
needs to be taken when considering where a medicine can be safely administered. For
example the term clinic has different connotations depending upon the country. For this
reason, the type of equipment needed may be specified rather than a location, e.g. use in a
setting where resuscitation equipment is available.
For classification as subject to special medical prescription the following factors should be
taken into account:
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b) Spontaneous report
Are those NOT derived from any organized data collection scheme, they are unsolicited
communication by a healthcare professional or consumer to a company, regulatory authority or
other organization (e.g. WHO, a regional center, a poison control center) which fulfills the
following three conditions:
it describes one or more suspected adverse reactions in a patient;
the patient was given one or more medicinal products;
it does not derive from a study or any organized data collection scheme.
Healthcare professionals or consumers may be stimulated to report a suspected adverse
reaction by several situations including:
a Direct Healthcare Professional Communication;
Early Post-Marketing Phase Vigilance (EPPV);
a report in the press;
direct questioning of healthcare professionals by company representatives.
In these circumstances, provided the report meets the three conditions above, it should be
considered a spontaneous report.
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Reporting of ICSRs (whether spontaneous or solicited) with regard to the reporting time frames
may be:
This Part of the guidelines will explain the different reporting requirement for the ICSRs of
suspected adverse reactions as follow:
Spontaneous reports
For suspected adverse reactions requiring expedited reporting, further explanation is provided
in this Chapter, section 4.2.
Reporting requirements in special situations, including obligations of the Applicant during the
period between the submission of the Marketing Authorization application and granting of the
Marketing Authorization, are described in this Chapter, section 4.3.
All suspected adverse reactions (although previously submitted to EPVC) should be included
also in the Periodic Safety Update (PSUR) further explanation is provided in chapter I.5.
Solicited reports
Suspected adverse reactions derived from Post Authorization Safety Studies (PASS) are
explained in chapter I.6
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with the authorized Summary of Product Characteristics (SPC) and/or any other conditions laid
down for marketing of the product in accordance with applicable legal requirements.
When a MAH receives an ICSR where the invented name of the medicinal product is not specified
but the active substance is included in any of the medicinal products for which a marketing
authorization is held, the MAH should assume that the report may relate to their product.
Spontaneous reports of adverse reactions received from Healthcare Professionals should be
reported by the MAH if:
the Healthcare Professional has made a statement that a causal relationship between the event
and the medicinal product is considered to be at least a reasonable possibility; or if
the Healthcare Professional has not made any statement on the suspected causal relationship or
has stated that the causal relationship is unknown; or if
If the Healthcare Professional has made an explicit statement that a causal relationship between the
medicinal product and reaction has been excluded and the MAH agrees with this, the event should
not be reported.
When the MAH is aware that a Healthcare Professional may have reported a reaction to one of
their products directly to EPVC, the MAH should still report the reaction, informing EPVC that the
report may be a duplicate of a previous report. In this situation, it is essential for the MAH to
provide all the available details including all case identification numbers allocated to the case, in
order to aid identification of the duplicate case. For further guidance on reporting of potential
duplicates, refer to Section A.1.11 Other case identifiers in previous transmission of ICH E2B
(M) (see Annex 4).
The MAH is expected to validate all adverse reactions reported by Healthcare Professionals to
ensure, prior to reporting to EPVC, that the minimum information required is included in the
report:
An identifiable Patient (see Section B.1 Patient characteristics of ICH E2B(M) (see Annex
4);
The Patient may be identified by initials, patient number, date of birth, age, age group or sex.
The information should be as complete as possible.
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At least one suspected active substance/medicinal product (see Section B.4 "Drug(s)
information" of ICH E2B(M) (see Annex 4);
At least one suspected adverse reaction (see Section B.2 "Reactions(s)/event(s)" of ICH E2B
(M) (see Annex 4).
Reports should be followed-up to obtain additional information relevant to the case as necessary,
and relevant follow-up information should be reported to EPVC.
All available clinical information relevant to the evaluation of the adverse reaction should be
provided.
For reports on adverse reactions from Patients/Consumers, (see Chapter I.4, Section 2.2.5). If
ICSRs, which do not qualify for expedited reporting as outlined in this Chapter, provide
information that may lead to a change in the known risk-benefit balance for the product, this
possible change should be notified to EPVC without delay.
Adverse reactions identified from the worldwide-published scientific literature should also be
reported.
4.2.1. Reporting Time Frames
The MAH should transmit all ICSRs requiring expedited reporting promptly and no later than 15
calendar days from receipt. This applies to initial and follow-up information, while other reports
that do not require expedited reporting should be reported to EPVC within 90 days.
The minimum information that should be included in the case:
An identifiable Patient;
The Patient may be identified by initials, patient number, date of birth, age, age group or sex.
The information should be as complete as possible.
The date the MAH becomes aware of a case which fulfills the minimum information stated above
should be considered day 0. The same applies if new information on the case is received by the
MAH, i.e. the reporting time clock begins again for the submission of the follow up report from
the day the MAH receives relevant follow-up information.
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The clock for expedited reporting starts (day 0) as soon as this minimum information has been
brought to the attention of any personnel of the MAH or an organization having a contractual
arrangement with the MAH, including medical representatives.
The individual cases described in the worldwide scientific literature, if cases occurring within
Egypt, for reporting purpose; the clock starts (day 0) with awareness of a publication containing
this minimum information by any personnel of the MAH or an organization having a contractual
arrangement with the MAH, including medical representatives.
Contractual arrangements may be made with a person or organization to perform literature
searches and/or report relevant individual cases (cases occurring within Egypt) to EPVC. If
another person or organization is performing these tasks, explicit procedures and detailed
agreements should exist between the MAH and this person or organization to ensure that the MAH
is promptly made aware of any individual cases described in the worldwide scientific literature to
ensure that the MAH can comply with their reporting obligations.
In general, where the MAH has set up contractual arrangements with a person or organization for
e.g. the marketing of, or research on a medicinal product authorized to this MAH, the clock starts
as soon as any personnel of the MAH or the other person/organization receives the minimum
information that constitutes a reportable case. Explicit procedures and detailed agreements should
exist between the MAH and the person/organization to ensure that the MAH can comply with his
reporting obligations (see Chapter I.1).
4.2.2. Requirements by Reporting Source
Generally reporting requirement for suspected adverse reaction goes according to the following
rules depending on the seriousness & geographic source:
Reports of all serious adverse reactions occurring within Egypt should be reported on an
expedited basis (i.e. within 15 calendar days), to EPVC. These reports should also be included
in the PSURs (see Chapter I.5);
Non-serious adverse reactions occurring inside Egypt should be reported within 90 days. These
reports should also be included in the PSURs (see Chapter I.5);
Reports on all adverse reactions occurring outside Egypt should be reported only on the
Periodic Safety Update Reports (PSURs) in accordance with Chapter I.5.
4.2.2.a.
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For reporting purposes, any suspected transmission via a medicinal product of an infectious
agent is also considered a serious adverse reaction and therefore should be reported in
expedited manner (see Chapter I.4.3.8).
Non-serious adverse reactions occurring within Egypt should only be reported in an expedited
manner on EPVC request and otherwise these non-serious reactions are to be reported together
with all their relevant follow-up information and final assessments within 90 days, as well it
should be included in the Periodic Safety Update Reports
ii) Individual Case Safety Reports on adverse reactions occurring outside Egypt
For all medicinal products, reports on ALL adverse reactions occurring outside Egypt
(whatever the source of the report) should be reported only on the Periodic Safety Update
Reports (PSURs) in accordance with Chapter I.5.
This may include:
All unexpected serious adverse reactions and any suspected transmission via a medicinal
product of an infectious agent occurring outside Egypt.
Serious unexpected adverse reactions and any suspected transmission via a medicinal product
of an infectious agent initially reported by a Healthcare Professional and subsequently
transmitted by a regulatory authority outside Egypt to the MAH.
Serious expected adverse reactions occurring outside Egypt Non-serious adverse reactions
occurring outside Egypt .
4.2.2.b.
Individual case reports from the worldwide literature are considered to be reports of which the
MAH should be reasonably aware and have knowledge of.
The MAH is therefore expected to maintain awareness of possible publications by accessing a
widely used systematic literature review and reference database (e.g. Medline, Excerpta Medica or
Embase) no less frequently than once a week. In addition, company offices are required to be
aware of publications in local journals and bring them to the attention of the QPPV as appropriate.
Cases of adverse reactions from the scientific and medical literature, including relevant published
abstracts from meetings and draft manuscripts, should be reviewed to identify individual cases
which might qualify for expedited reporting.
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As required by legislation, the MAH should report within 15 calendar days published serious
adverse reactions associated with the use of the active substance(s) of their medicinal products, as
relevant to the categories identified in Chapter I.4, Section 2.2.
If the medicinal product source and/or the invented name is not specified and ownership of the
product cannot be excluded on the basis of the active substance(s), formulation or route of
administration, the MAH should assume that it is one of their products the publication refers to,
although the report should indicate that the specific product source and/or the invented name was
not identified.
If multiple medicinal products are mentioned in the publication, a report should be submitted only
by the MAH(s) of the product(s) which is (are) identified by the publications author(s) as having
at least a possible causal associated with the reaction.
4.2.2.c.
The MAH should regularly screen websites under their management or responsibility, for potential
reports on adverse reactions. The MAH is not expected to screen external websites for information
on adverse reactions. However, if a MAH becomes aware of an adverse reaction on any other
website the MAH should review the case and determine whether it should be reported in expedited
manner in accordance with Chapter I.4, Sections 2.2.a and 2.2.e.
The MAH should consider utilizing their websites to facilitate adverse reaction collection, e.g. by
providing adverse reaction forms for reporting or by providing appropriate contact details for
direct communication. In relation to such reported adverse reactions, identifiability of the reporter
and Patient refers to the existence of actual people (see Chapter I.4, Section 2.2.a).
4.2.2.d.
Reporting requirements for cases derived from organized data collection systems (which include
clinical trials, post-authorization studies, registries, post-authorization named-patient use
programs, other patient support and disease management programs, surveys of Patients or
Healthcare Providers, and information gathering on efficacy or patient compliance) differ
depending on whether they are derived from interventional or non-interventional studies.
i) Interventional Studies
Adverse reactions arising from interventional studies carried out within Egypt on medicinal
products for Human Use should be reported. The investigator shall report all serious events
immediately to the sponsor except for those that the protocol or investigators brochure
identifies as not requiring immediate reporting.
Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety
evaluation shall be reported to the sponsor according to the reporting requirements within the
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time periods specified in the protocol. The investigator shall supply the sponsor and the Ethics
Committee with any additional requested information, notably for reported deaths of a subject.
The sponsor shall keep detailed records of all adverse events and he shall ensure that all
relevant information is submitted to EPVC according to the following:
All relevant information of about all adverse events to be submitted on request to EPVC.
Suspected unexpected serious adverse reactions (SUSARs) is recorded and shall be reported to
EPVC as soon as possible but within a maximum of 15 calendar days of his first knowledge
SUSARs that are fatal or life-threatening is recorded and reported as soon as possible to EPVC,
and in any case no later than 7 calendar days after his knowledge of such a case, and that
relevant follow-up information is subsequently communicated within an additional 8 days.
The sponsor shall provide EPVC every year with a listing of all suspected serious adverse
reactions which have occurred over this period. For reporting of adverse reactions in the
Periodic Safety Update Reports (PSURs), see Chapter I.5.
When a Consumer submits medical documentation that supports the occurrence of the adverse
reaction, this should be considered sufficient to report the individual case if it provides the
minimum information (see Chapter I.4, Section 2).
For requirements to reflect Consumer reports in Periodic Safety Update Reports see Chapter
I.5. For requirements in relation to reporting of outcomes of use of medicinal products during
pregnancy, originating from Consumers, see Chapter I.4, Section 3.3.
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Medically unconfirmed adverse reactions should not be reported to EPVC on expedited basis.
4.2.2.f.
If a MAH becomes aware of a case report from non-medical sources other than those mentioned in
the last section above e.g. the lay press or other media, every attempt should be made to obtain the
minimum information that constitutes an individual case (see Chapter I.4, Section 2) and to followup the case as for reports from a Patient/Consumer.
4.2.3. Data Elements for the Report
The principles in the ICH-E2D Guideline and ICH E2B (M) Guideline (see Annex 4) should be
followed.
The minimum information constituting a case is:
An identifiable Patient;
The Patient may be identified by initials, patient number, date of birth, age, age group or sex.
The information should be as complete as.
It is essential for the MAH to provide as many data elements as possible for cases of adverse
reactions to facilitate assessment. The MAH is expected to follow-up all reports of serious adverse
reactions to their medicinal product(s) to obtain comprehensive information where available.
Additional information not available at the time of the initial report should be provided in the form
of follow-up reports.
The suspect, interacting and/or concomitant active substance(s)/invented name of the suspect
product(s) should be reported in accordance with ICH-E2B(M) (see Annex 4). The MAH should
report ICSRs to EPVC in English language.
The MAH may comment on the causal relationship between the suspect product(s) and the
reaction(s) reported and should provide the criteria on which he has made the assessment in field
B.4.k.18 Relatedness of drug to reaction(s)/event(s) of ICH E2B(M).
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In situations where ICSRs impact on the known risk-benefit balance of a medicinal product, the
MAH should indicate in a separate letter to EPVC what action is proposed in relation to the
marketing authorization, the Summary of Product Characteristics and Patient Information Leaflet.
This should in addition be recorded in field B.5.4 Senders comments of ICH-E2B (M).
4.2.4. Method of Reporting
Electronic reporting of adverse reactions is mandatory, save in exceptional circumstances.
Reporting in the period between the submission of the marketing authorization application and
the granting of the marketing authorization;
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4.3.1. Reporting in the Period between the Submission of the Marketing Authorization
Application and the Granting of the Marketing Authorization
In the period between submission of the marketing authorization application and the authorization,
information that could impact on the risk-benefit balance may become available to the Applicant.
It is the responsibility of the Applicant to ensure that this information is immediately submitted to
EPVC.
4.3.2. Reporting Following Suspension or Withdrawal of the Marketing Authorization for
Safety or Commercial Reasons
Reporting requirements remain following suspension of the marketing authorization of a medicinal
product (ICSR & PSUR). Where a marketing authorization is withdrawn or revoked, the former
MAH is encouraged to continue to report in line with Chapter I.4 to e.g. facilitate review of
delayed onset adverse reactions and retrospectively notified cases. It may be appropriate to
continue submission of PSURs after withdrawal or revocation of the marketing authorization. An
agreement should be made on a case-by-case basis with EPVC.
4.3.3. Reporting of Outcomes of Use of a Medicinal Product During Pregnancy
The MAH should follow-up all reports from Healthcare Professionals relating to pregnancies
where the foetus may have been exposed to one of his medicinal products (either through maternal
exposure or transmission of a medicinal product via semen following paternal exposure).
Where reports originate from Consumers, reasonable attempts should be made to follow-up via the
Patients Healthcare Professional. When a Consumer submits medical documentation that supports
the occurrence of a suspected adverse reaction, this should be considered sufficient to report the
case if it provides the minimum information (see Chapter I.4, Section 2).
When an active substance, or one of its metabolites, has a long half-life, this should be taken into
account when considering the possibility of fetal exposure (i.e. medicinal products taken before
conception need to be considered) (see Annex 3.1.2).
Individual cases with an abnormal outcome in association with a medicinal product should be
reported on an expedited basis, following the reporting requirements outlined in Chapter I.4 and
in accordance with the Guideline on Exposure to medicinal products During Pregnancy: Need for
Post-Authorization Data (see Annex 3.1.2) and the ICH E2B(M) Guidelines (see Annex 4).
This refers especially to:
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I.4, section 2. For electronic reporting, such cases should be classified as serious, and.
Seriousness criteria should be set to Other medically important condition (see ICHE2B (M) in
Annex 4).
The requirement to apply MedDRA coding (see Annex 4) is also relevant to the reporting of cases
of suspected transmission of an infectious agent.
Any organism, virus or infectious particle (e.g. prion protein transmitting Transmissible
Spongiform Encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent.
A transmission of an infectious agent may be suspected from clinical symptoms or laboratory
findings indicating an infection in a patient exposed to a medicinal product. As in the case of
suspected adverse reactions and adverse reactions, the terms suspected transmission and
transmission are considered synonymous. Confirmation of contamination (including inadequate
inactivation/attenuation of infectious agents as active substances) of the concerned medicinal
product increases the evidence for transmission of an infectious agent.
Signals arising from case reports on suspected transmission of an infectious agent should be
investigated as for other adverse reactions.
Suspected or confirmed quality defect of medicinal products should be reported to EPVC. Any
contamination of a medicinal product should be considered serious and is likely to be classified as
a Class 1 or Class 2 Product Defect (see Annex 6).
The potential for transmission of an infectious agent via a medicinal product should also be
addressed in the Risk Management Plan.
Any serious adverse events related to the use of medicinal products derived from human blood or
human plasma should be reported to EPVC.
4.3.9. Reporting in Relation to Overdose, Abuse and Misuse
The MAH should collect any available information on overdose, abuse and misuse related to his
products. Reports of overdose, abuse and misuse should be routinely followed up to ensure that
information is as complete as possible with regard to early symptoms, treatment and outcome. The
MAH should report cases of overdose, abuse and misuse that lead to serious adverse reactions on
an expedited basis in accordance with the requirements in Chapter I.4 section 2. This includes
cases of intended suicide. The MAH should continuously monitor and evaluate the potential
impact of overdose, abuse and misuse on the overall risk-benefit balance of the medicinal product.
The potential for overdose, abuse and misuse and the associated risks should also be addressed in
the Periodic Safety Update Reports and the Risk Management Plan.
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When launch dates are planned and once the product is marketed, this information should be
reflected in the upcoming PSUR
Generic products should have the same PSUR submission periodicity as the Corresponding
originator product. In this context it should be highlighted that biosimilars are not considered
generic products hence, for each imported biological product the cycle of PSUR submission restarts according to its IBD (not its originator IBD). For biological products manufactured in Egypt
the cycle of PSUR submission starts from the Egyptian Birth Date (EBD) which is the date of first
marketing authorization granted for this biological product in Egypt to the MAH.
Moreover, review of the periodicity is also part of the Risk Management Plan and its assessment
(see Chapter I.3).
There may be situations where exceptionally the submission of 6-monthly and subsequent yearly
PSURs may be re-started, or where other amendments of the periodicity are required. This is
further explained in Chapter I.5, Section 2.4.c.
If the MAH considers, on the basis of the data included in the PSUR, that amendment of the
Summary of Product Characteristics (SPC) is necessary, a variation application should be
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submitted with the PSUR, or where this is not possible, a timetable for submission should be
proposed at the time of PSUR submission.
PSUR should be submitted on CD as searchable PDF file, in conjunction with hard copy of signed
submission letter.
5.2.2. One Periodic Safety Update Report for Products Containing an Active Substance
Authorized to One MAH
It is recommended that information on all indications, dosage forms, routes of administration and
regimens for a given active substance for medicinal products authorized to one Marketing
Authorization Holder should be included in a single PSUR, with a single data lock point common
for all aspects of product use to facilitate a consistent, broad-based examination of the safety
information for the active substance(s) in a single document.
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When relevant and possible, data relating to a particular indication, dosage form, route of
administration or dosing regimen should be presented in separate sections within the body of the
PSUR and any safety concerns addressed accordingly without preparing a separate PSUR (e.g. a
section dedicated on pediatric use summarizing safety as well as exposure information).
In exceptional cases, EPVC or the MAH may consider it appropriate to have a separate PSUR. In
such cases, agreement should be obtained at the time of authorization or during the postauthorization phase, as applicable. Examples include:
Products authorized through line extensions to existing medicinal products (e.g. an active
substance in two or more different formulations for systemic versus topical administration)
with cross-reference between PSURs, if appropriate (see Chapter I.5, Section 2.4.c);
Fixed combinations, where options include either a separate PSUR for the combination with
cross-reference to the single-substance PSUR(s) or inclusion of the fixed combination data
within one of the single-substance PSURs.
If a subsequent marketing authorization is granted to a MAH for a product which contains the
same active substance as one previously granted to the same MAH, the data lock points used for
the PSURs for the first product should normally be used for the following joint PSURs covering
the first and all subsequent products.
5.2.3. Products Authorized to More Than One MAH
Where a product is authorized to more than one MAH, in the case of multiple applications,
submission of common PSURs is acceptable provided that the products remain identical in all
respects apart from their invented names and that the PSURs are submitted separately by each
MAH. The data lock point should be based on the birth date used for the first authorized product.
The submission cover letter should confirm that the data in these PSURs are identical.
Generic products should preferably have the same PSUR submission periodicity as the
Corresponding originator product (see Chapter I.5, Section 2.4.c). It is generally considered
acceptable that MAHs for generic products collaborate on the preparation of PSURs. However,
each MAH remains responsible for the appropriate submission of PSURs for their products. Where
common PSURs are submitted, the MAHs should confirm in writing that the data in these PSURs
are identical.
MAHs who have contractual arrangements in place but opt not to submit common PSURs, should
ensure that all data which may meaningfully contribute to the safety analysis and influence any
proposed or effected changes in the Product Information of the medicinal product authorized to the
reporting MAH, should be included, with the source indicated, and discussed in the PSUR, even if
it is known that they are included in another MAHs PSUR.
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When a medicinal product is to be authorized in Egypt, the PSURs are required to be prepared
and submitted in accordance with the regular international periodicity for PSUR submission,
hence PSURs submission for medicinal products authorized in Egypt are required to fit in the
following cycle according to their IBDs or HBD (once they grant the Egyptian authorization
even if not marketed yet): ;
6-monthly PSUR submissions should be continued until two full years of international
marketing has been gained;
yearly PSURs for the following two years; and
thereafter PSURs should be submitted at 3-yearly intervals;
in addition, PSURs should be submitted immediately upon request from EPVC.
at the authorization (registration) phase (when applicable)
at the renewal of authorization (re-registration) phase
The first PSUR should have a data lock point within 6 months after granting of the first marketing
authorization (IBD).
The date of initial placing on the Egyptian market is the date of launch, for the first time.
Each PSUR should cover the period of time since the last PSUR and should be submitted within 60
days after the data lock point.
Exceptionally, a MAH may make a special request to EPVC for 30 additional calendar days to
submit a PSUR. Ideally, this request should be made before the data lock point. EPVC should
respond as rapidly as possible. The basis for such a request should be justified and could include:
a large number of case reports for the reporting period, provided that there is no new
significant safety concern;
safety concerns raised by EPVC in the previous PSUR for which the MAH is preparing
additional or further analysis in the next PSUR; and/or
safety concerns identified by the MAH that might require additional or further analysis.
The MAH should make such a request only for the specific PSUR in question and not for
subsequent PSURs. Subsequent PSURs will generally be expected to be submitted on the
appropriate date in line with their original periodicity.
Because the renewal is an independent process, it does not change the data lock point and
submission schedule for the PSURs. It should be noted that re-assessment of the risk-benefit
balance at the time of renewal is an opportunity to review and, if necessary, change the periodicity
PSUR.
When yearly or 3-yearly PSURs are due for submission, multiple 6-monthly or yearly PSURs are
acceptable, provided that the MAH submits a PSUR Summary Bridging Report, the content of
which is described in Chapter I.5, Section 4. It should be noted that in such cases, the MAH should
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not send 6-monthly or yearly PSURs 60 days after the data lock points of these 6-monthly or
yearly PSURs, but should send them only at the required due date (yearly or 3-yearly).
If a time gap occurs between the data lock point of a regular PSUR and a request from EPVC (e.g.
renewal, Risk-Benefit Review, ad hoc PSUR request), a PSUR Addendum Report should also be
submitted (see Chapter I.5, Section 5). For a PSUR that spans longer time intervals, e.g. 3 years, an
Addendum Report would only be considered appropriate if the time since preparation of the 3-year
PSUR and the locally required report is greater than 6 months.
For PSURs requested for immediate submission by EPVC on an ad hoc basis, the MAH should
liaise with EPVC to agree the PSUR submission date, depending on the urgency of the issue.
5.2.4.b.
The MAH should submit safety data with the renewal application at least 6 months before the
expiry date of the marketing authorization in Egypt. For the submission of safety data as part of the
application for renewal of the marketing authorization, the PSUR concept should be used. The
MAH should lock the data no more than 60 days before submitting the PSUR.
The data lock point for submission of safety information should be at 9 years and 4 months
following the marketing authorization date. Renewal applications may be submitted earlier than 6
months before the expiry date of the marketing authorization.
For the purpose of the renewal application, the MAH should submit:
the PSUR, or the PSUR plus a PSUR Addendum Report (see Chapter I.5, Section 5) or plus
line-listings and/or summary tabulations, or only a PSUR Addendum Report, or only
linelistings and/or summary tabulations, covering the period since the data lock point of the
last PSUR (e.g. for the first renewal, the safety data of this PSUR or Addendum Report
together with the PSURs previously submitted should cover a period of 9 years and 4 months
since the marketing authorization); and
a PSUR Summary Bridging Report, bridging all PSURs (including those already submitted)
covering the period of 9 years and 4 months. Alternatively, the information which corresponds
by its content with the PSUR Summary Bridging Report may be included in the Clinical
Overview, to be submitted with the renewal application. It is accepted that previously
submitted PSURs should not be re-submitted, provided that a list of original submission dates
is appended to the Summary Bridging Report.
The second renewal application should discuss PSURs data covering a 9 year period since the data
lock point of the PSUR(s) submitted with the first renewal application.
Because the renewal is an independent process, it does not change the periodicity and submission
dates for PSURs due as part of pharmacovigilance reporting requirements. It should be noted that
reassessment of the risk-benefit balance at the time of renewal is an opportunity to review and, if
necessary, change the PSUR periodicity.
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The MAH may discuss the requirements for PSURs for the renewal applications with EPVC, and
agree on the appropriate PSUR documentation required.
5.2.4.c.
A priori, a line-extension triggers the restart of the regular PSUR periodicity, unless a different
periodicity has been agreed as a condition for the granting of the marketing authorization.
However, in many cases, there will be no need to restart the regular PSUR periodicity following
the line-extension, as data for the newly authorized product may be addressed in the PSURs
submitted according to the existing submission schedule. A justification for continuing the existing
submission schedule should be provided by the MAH as part of the line-extension application, and
the conditions for the authorization will include any amendment of the periodicity, if required, as
part of the outcome of the application evaluation.
Where separate PSURs for the product approved through the line-extension are considered
appropriate, these should be submitted in accordance with the authorization date of the newly
approved product by starting the regular PSUR periodicity, while the PSUR submission for the
previously authorized product(s) continues according to the existing submission schedule. These
requirements should be reflected in the conditions for the authorization. If/when separate PSURs
are no longer considered necessary; data relevant to the product approved through the lineextension should be incorporated in a single PSUR covering all related products.
The addition of a paediatric indication for an existing medicinal product is an example of a lineextension which would result in re-starting the regular PSUR periodicity following the
authorization date of the newly approved product (see Annex 3.1.3).
For newly authorized generic products or products authorized on the basis of informed consent
applications, application for submission of PSURs on a 3-yearly basis may be included in the
authorization application. PSURs for such products should preferably have the same data lock
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points as the corresponding originator product (see Chapter I.5, Section 2.4.c). Such applications
will be assessed on a case-by-case basis by EPVC.
Circumstances where more frequent PSUR submission may be required include:
In some circumstances, e.g. for biological products, a change in the manufacturing process may
require close monitoring of possible clinical impact in terms of safety. Therefore, the conditions
under which the related variation of the marketing authorization is granted may include a re-start
of the regular PSUR periodicity.
If EPVC considers it appropriate to amend the PSUR periodicity and submission schedule, this
should be clearly communicated to the MAH.
5.2.4.d.
Medicinal products, which are also authorized outside Egypt, will have an International Birth Date
(IBD).
The IBD is the date of first marketing authorization of a medicinal product granted to the MAH (or
a contractual partner of the MAH) anywhere in the world. For practical reasons, the IBD may be
defined as the last day of the month in which this first authorization date falls.
The Egyptian Birth Date (EBD) is the date of first marketing authorization granted for the
medicinal product in Egypt to the MAH (see Glossary in Annex 1.1).
In order to harmonize PSUR submissions internationally, the MAH may use the IBD to determine
the dates of the data lock points and the international periodicity for the PSUR submission
schedule.
5.2.5. Reference Safety Information
An objective of a PSUR is to establish whether information recorded during the reporting period is
in accordance with previous knowledge of the medicinal products safety, and to indicate whether
changes should be made to the Product Information or the Risk Management Plan. Reference
information is needed to carry out this comparison.
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Having one reference safety document would facilitate a practical, efficient and consistent
approach to the safety evaluation and make the PSUR a unique report also accepted in other
regions of the world.
It is common practice for MAHs to prepare their own Company Core Data Sheet (CCDS), which
includes material relating to safety, indications, dosing, pharmacology and other information
concerning the product. A practical option for the purpose of the PSUR is for each MAH to use, as
a reference, the safety information contained within the CCDS, which is referred to as Company
Core Safety Information (CCSI).
For the purposes of PSURs, the CCSI forms the basis for determining whether an adverse reaction
is already listed or is still unlisted (listed and unlisted are terms that are introduced to distinguish
them from the usual terminology of expectedness, which is used in association with the authorized
Product Information).
The Summary of Product Characteristics (SPC) continues to be the reference document upon
which expectedness is based for the purpose of expedited post-authorization safety reporting in
Egypt.
It is important to highlight meaningful differences between the CCSI and SPC in the cover letter
accompanying the submission of the PSUR. The SPC should also be provided.
In case of CCSI updates the one to be attached with the PSUR are:
1. For 6-monthly and yearly PSURs the version of the CCSI in effect at the beginning of the
period covered by the PSUR should be used as the reference information.
2. However, there may be valid reasons to use the CCSI in effect at the end of the period:
When producing a PSUR covering a period of more than one year or a PSUR Summary
Bridging Report, it is often impractical to base the analysis of listedness on the CCSI that
was in effect at the beginning of the period. There may be considerable variation in
listedness over the reporting period. Therefore, the latest CCSI in effect at the end of the
period may be used for PSURs covering a longer period.
For PSURs covering a period of more than one year, when listedness is assessed at the time
of PSUR preparation after the data lock point, it is generally considered appropriate to use
the version of the CCSI in place at the end of the reporting period as the reference
document, as long as that choice is made clear in the PSUR.
Whether the CCSI valid at the beginning or at the end of the period covered in the PSUR is
used, the MAH should ensure that all changes to the CCSI made over this period are
described in the relevant section of the PSUR entitled Changes to the Reference Safety
Information.
3. MAHs assessing listedness at case entry or on an ongoing basis throughout the reporting period
should include the current version of the CCSI and comment on the reasons for any change in
listedness assessment over time. In both cases, changes added since the previous PSUR should
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be explained in the PSUR sections Changes to Reference Safety Information (section 3.5)
and/or Overall Safety Evaluation (section 3.10).
The Reference Safety Information to be used for PSURs for generic medicinal products based on
IBD should consist of the common safety information that is included in all current SPCs of the
concerned generic medicinal product, as authorized in Egypt at the time of the data lock point. In
addition, a summary of the other safety information that was not included in all SPCs should be
submitted. The MAH should indicate in the PSUR which changes to the Reference Safety
Information as used are considered necessary on the basis of the data examined in the PSUR.
5.2.6. Presentation of Data on Individual Cases
5.2.6.a.
Sources of Information
Generally, adverse reaction data from the following sources are potentially available to the MAH
and should be included in the PSUR:
Adverse reaction reports notified directly to the MAH (or through schemes under its control):
o
o
o
Literature
Adverse reaction reports received from regulatory authorities worldwide:
o
The reaction terms used in the PSUR should be in accordance with the MedDRA terminology (see
Annex 3.2.1).
Whenever possible, the original reporters reaction terms should be used to describe the adverse
reaction. However, when the original reporters terms are not medically appropriate or meaningful,
the MAH should use the best alternative compatible reaction terms from MedDRA to ensure the
most accurate representation possible of the original terms. Under such circumstances, the
following should be borne in mind:
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In order to be able to make it available on request, the verbatim information supplied by the
original reporter should be kept on file (in the original language and/or as a medically valid
English translation, if applicable).
In the absence of a diagnosis by the original reporter, a suggested diagnosis for a symptom
complex may be made by the MAH and used to describe the case, in addition to presenting the
reported individual signs, symptoms and laboratory data.
If the MAH disagrees with a diagnosis that is provided by the original reporter, such
disagreement may be indicated within the line-listing of cases (see Chapter I.5, Section 2.6.c).
The MAH should report and try to understand all information provided within a case report.
An example is a laboratory abnormality not addressed/evaluated by the original reporter.
Therefore, when necessary and relevant, two descriptions of the signs, symptoms or diagnosis
could be presented in the line-listing: first, the reaction as originally reported; second, when it
differs, the MAHs medical interpretation (identified by asterisk or other means).
5.2.6.c.
Depending on their type or source, available adverse reaction cases should be presented as
linelistings and/or as summary tabulations (see Table below).
A line-listing provides key information but not necessarily all the details customarily collected on
individual cases; however, it does serve to help EPVC identify cases which they may wish to
examine more completely by requesting full case reports.
The MAH should prepare line-listings of consistent structure and content for cases directly
reported to him (or under his control), including those from persons and organizations with whom
the MAH has set up contractual arrangements, as well as those received from worldwide
regulatory authorities (see Chapter I.5, Section 2.6.a). They should usually do the same for
published cases (usually well documented; if not, follow-up with the author may be possible).
However, inclusion of individual cases from second- or third-hand sources, such as persons or
organizations with whom the MAH has contractual arrangements and special registries may not be
possible without standardization of data elements, or appropriate due to the paucity of information,
and may represent unnecessary re-entry/re-processing of such information by the MAH. Therefore,
summary tabulations or possibly a narrative review of these data are considered acceptable under
these circumstances.
In addition to individual case line-listings, summary tabulations of adverse reaction terms for
signs, symptoms and diagnoses across all patients should usually be presented to provide an
overview.
Such tabulations should be based on the data in the line-listings (e.g. all serious adverse reaction
and all non-serious unlisted adverse reaction), and also on other cases for which line-listings are
not requested (e.g. non-serious listed adverse reactions). Details are found in model PSUR Cases
presented as Line-listing and Cases presented as Summary tabulation.
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Source
1.
Spontaneous reporting*,
Studies
Post-authorization safety
studies and other studies
Compassionate use
programmes
2. Literature
Type of Case
Only
Summary
Tabulation
Line-Listing
and Summary
Tabulation
serious
yes
non-serious unlisted
yes
non-serious listed
yes**
yes
serious
yes
serious
yes
non-serious unlisted
yes
yes
3. Other sources
Regulatory authorities
serious
Contractual partners***
serious
yes
Registries
serious
yes
serious
yes
Epidemiological databases
serious
yes
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The worldwide marketing authorization status (including a list of countries where the product
is authorized/marketed and the authorized indications;
Other relevant regulatory information related to the period covered by the PSUR (e.g. any
urgent safety restriction should be highlighted);
Exposure data (National & International)
Number of new case reports received during the period covered by the PSUR and the
cumulative numbers;
Particular issues and safety concerns investigated;
Overall findings of the PSUR;
Conclusions.
When the MAH has performed a review of one or several specific safety concern(s), this should be
stated in this Executive Summary (as well as the nature of safety concerns that have been
reviewed).
5.3.2. PSUR section Introduction
The MAH should briefly introduce the product so that the PSUR stands alone but is also placed
in perspective relative to previous PSURs and circumstances.
Reference should be made not only to product(s) covered by the PSUR but also those excluded.
Exclusions should be explained; for example, they may be covered in a separate PSUR (e.g. for a
combination product).
If it is known that a PSUR on the same product(s) will be submitted by another Marketing
Authorization Holder and some of whose data are included in the PSUR the possibility of data
duplication should be noted.
Information about the medicinal product International Birth Date (IBD), should be included here,
IBD is the date of the first marketing authorization for the product granted to this MAH in any
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country in the world. For administrative convenience, if desired by the MAH, the IBD can be
designated as the last day of the same month.
5.3.3. PSUR section Worldwide Marketing Authorization Status
This section of the PSUR provides cumulative information.
The following information should be provided for any indication, as a table, for all countries
where a regulatory decision about marketing has been made related to the following (Annex 5.2.1,
PSUR template, Table 1):
Dates of marketing authorization and subsequent renewal (where PSURs are common for
identical products with different invented names, or in the case of generic medicinal products,
the list of the dates should cover all products separately);
Any qualifications surrounding the authorization, such as limits on indications if relevant to
safety;
Treatment indications and special populations covered by the market authorization, when
relevant;
Lack of approval, including explanation, by worldwide regulatory authorities;
Withdrawal by the company of an application for authorization submission if related to safety
or efficacy;
Dates of launch (where PSURs are common for identical products with different invented
names or in the case of generics, the listing of the dates should cover separately all products);
Dates when the marketing authorization has been revoked/withdrawn or dates when the
marketing or marketing authorization has been suspended either by a regulatory authority or
voluntarily by the MAH;
Invented name(s).
Dosage form
Registration No.
Typically, indications for use, populations treated (e.g. children vs. adults) and dosage forms will
be the same in many or even most countries where the product is authorized. However, when there
are important differences, which would reflect different types of patient exposure, such
information should be noted. This is especially true if there are meaningful differences in the
newly reported safety information that are related to such different exposures.
If more convenient and useful, separate regulatory status tables for different product uses or forms
should be utilized.
Country entries should be listed in chronological order of regulatory authorizations. For multiple
authorizations in the same country (e.g., new dosage forms), the IBD for the active substance and
for all PSURs should be the first (initial) authorization date.
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Annex 5.2.1. Table 1, provides an example, with fictitious data for an antibiotic, of how such a
table might be organized. The product was initially developed as a solid oral dosage form for outpatient treatment of various infections.
5.3.4. PSUR section Update of Regulatory Authority or Marketing Authorization Holder
Actions taken for Safety Reasons
This section should include details on the following types of worldwide actions relating to safety
that were taken during the period covered by the PSUR and between data lock point and PSUR
submission:
The safety-related reasons that led to these actions should be described and documentation
appended when appropriate; any communication with Healthcare Professionals (e.g. Direct
Healthcare Professional Communication (DHPC), commonly called Dear Doctor Letter (DDL))
as a result of such action should also be described with copies appended.
However, for each one of those actions, even if it was not taken; a clear statement indicating that
should be included.
5.3.5. PSUR section Changes to Reference Safety Information
For 6-monthly and yearly PSURs, the version of the CCDS with its CCSI coming into effect at
the beginning of the period covered by the report should normally be used as the reference
information.
For a PSUR covering a period of over one year, the latest CCSI in effect at the end of the
period may be used (see Chapter I.5, Section 2.5).
The CCSI used as reference should be numbered, dated and appended to the PSUR and include the
date of the last revision. Changes to the CCSI, such as new contraindications, precautions,
warnings, adverse reactions or interactions, already made during the period covered by the PSUR,
should be clearly described, with presentation of the modified sections. The revised CCSI should
be used as the reference for the next PSUR and the next period (see also Chapter I.5, Section 2.5).
With the exception of emergency situations, it may take some time before intended modifications
are introduced in the Product Information. Therefore, during that period the amended reference
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document (CCSI) may contain more listed information than the existing Product Information in
many countries.
When meaningful differences exist between the CCSI and the safety information in the
official data sheets/product information documents approved in a country, a brief comment
should be prepared by the company, describing the local differences and their consequences
on the overall safety evaluation and on the actions proposed or initiated. This commentary
may be provided in the cover letter or other addendum accompanying the local submission
of the PSUR.
5.3.6. PSUR section Patient Exposure
5.3.6.a.
When adverse reaction data from clinical studies are included in the PSUR, the relevant
denominator(s) should be provided. For ongoing and/or blinded studies, an estimation of patient
exposure may be made.
5.3.6.b.
Market experience
Estimating patient exposure data for marketed medicinal products often relies on gross
approximations of in-house or purchased sales data or volume to determine patient exposure. This
is not always reliable or available for all products. For example, hospital-based (in-patient
exposure) data from the major monitoring sources are frequently unavailable. It may also be
difficult to obtain accurate data for medicinal products of which generic presentations are in use.
For non-prescription products, use is often on an as-required basis, and individual packages are
frequently used by multiple family members of different ages and weights.
Where possible, an estimate of patient exposure should cover the same period as the interim safety
data. While it is recognized that it is usually difficult to obtain and validate accurate exposure data,
an estimate of the number of patients exposed should be provided along with the method
used to derive the estimate. An explanation and justification should be presented if the number of
patients is impossible to estimate. In its place, other measures of exposure, such as patient-days,
number of prescriptions or number of dosage units are considered appropriate; the method used
should be explained. Given the difficulty of estimating cases, patient exposure should preferably
be provided as person-time of exposure (days, months, years). The MAH should be consistent in
its method of calculation across PSURs for the same product. If a change in the method is
appropriate, then both methods and calculations should be shown in the PSUR introducing the
change. If these or other more precise measures are not available, bulk sales (tonnage) may be
used. The concept of a Defined Daily Dose may be used in arriving at patient exposure estimates.
When possible and relevant, data broken down by sex and age (especially paediatric vs. adult)
should be provided.
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Pediatric population exposure should be broken down according to age groups. An estimate of use
outside the terms of the marketing authorization should be provided along with the method used to
provide the estimate.
Pregnancy exposure should also be estimated specially in the case of pregnancy registries using the
same data lock point as the PSUR.
When an observed pattern of case reports indicates a potential problem, details by country
including Egypt (with locally recommended daily dose) or other breakdowns (e.g. indication,
dosage form) should be presented if available.
When exposure data are based on information from a period that does not fully cover the period of
the PSUR, the MAH may extrapolate using the available data. If this is done it should be clearly
indicated what data were used and why it is valid to extrapolate for the PSUR period in question
(e.g. stable sales over a long period of time, seasonality of use of the product).
In a PSUR Summary Bridging Report, exposure should be presented including the full reporting
period and explaining any differences in this estimation from the simple sum of exposure estimates
included in the separate PSURs covered by the PSUR Summary Bridging Report. In addition,
cumulative exposure estimates should be presented (for further guidance see explanations provided
in the Risk Management Plan Template in Annex 5.1.1).
5.3.7. PSUR section Presentation of Individual Case Histories
This section should contain a description and analysis of selected cases containing new or relevant
safety information and grouped preferably by medically relevant headings/MedDRA System
Organ Classes (SOCs).
A description of the criteria used to select cases for presentation should be provided.
Follow-up data on individual cases may be obtained subsequent to their inclusion in a PSUR. If
such information is relevant to the interpretation of the case (e.g. significant impact on the case
description or analysis), the new information should be presented in the next PSUR, and the
correction or clarification noted relative to the earlier case description. Cases where follow-up
information is not considered to have any impact on the overall assessment of the case and has not
led to relevant coding changes for the case, do not need to be discussed in the body text of the
PSUR.
However, such cases should always be presented in cumulative tables and analyses if relevant.
With regard to the literature, MAHs should monitor standard, recognized medical and scientific
journals for safety information relevant to their products and/or make use of one or more literature
search/summary services for that purpose.
Published cases received from other sources (e.g. spontaneous reporting, studies) should only be
included once and literature citation should be provided regardless of the primary source.
With regards to spontaneous reports that originate from Patients/Consumers, MAHs should:
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5.3.7.a.
The types of cases referenced below should be included in the line-listings. Attempts should be
made to avoid duplicate reporting of cases from literature and regulatory sources.
All serious adverse reactions and non-serious unlisted adverse reactions from spontaneous
reporting;
All serious adverse reactions (attributable to the medicinal product by either investigator or
sponsor) available from post-authorization safety studies (PASS) and other studies (including
those which are part of the Risk Management Plan) or named patient/compassionate use;
All serious adverse reactions, and non-serious unlisted adverse reactions from the literature;
All serious adverse reactions transmitted to the MAH by worldwide regulatory authorities.
In addition, the types of cases referenced below should be included as line-listings in the form of
an annex to the PSUR:
Suspected transmission via a medicinal product of any infectious agent should be considered as a
serious adverse reaction (see Chapter I.4, Section 3.8).
Line-listing(s) (see Annex 5.2.1, Table 2 for Template) should include each Patient only once
regardless of how many adverse reaction terms are reported for the case. If there is more than one
reaction, they should all be mentioned but the case should be listed according to the most serious
adverse reactions (sign, symptom or diagnosis), as judged by the MAH.
It is possible that the same Patient may experience different adverse reactions on different
occasions (e.g. weeks apart during a clinical trial). Such experiences should be treated as separate
reports. Under such circumstances, the same Patient might then be included in a line-listing more
than once, and the line-listings should be cross-referenced when possible. Line-Listings should be
organized (tabulated) by body system (MedDRA System Organ Classes (SOCs)).
Where common PSURs are submitted, the line-listings should still reflect the invented name of the
medicinal product (or the active substance name if the invented name of the medicinal products is
not available) as reported by the original reporter.
The following headings should usually be included in the line-listings (see Annex 5.2.1, Table 2):
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Date of onset of the adverse reaction(s). If not available, best estimate of time to onset from
therapy initiation. For adverse reactions known to occur after cessation of therapy, estimate of
time lag if possible (may go in comments section);
Description of adverse reaction(s) as reported, and when necessary as interpreted by the MAH
in English (see Chapter I.5, Section 2.6.b);
Patient outcome (at case level) (e.g. resolved, fatal, improved, sequelae, unknown). This should
indicate the consequences of the adverse reaction(s) for the Patient, using the worst of the
different outcomes for multiple reactions;
Comments, if relevant (e.g. causality assessment if the manufacturer disagrees with the
reporter; concomitant medications suspected to play a role in the reactions directly or by
interaction; indication treated with suspect medicinal product(s); dechallenge/rechallenge
results if available). It should be used only for information that helps to clarify individual
cases.
Depending on the product or circumstances, it may be useful or practical to have more than one
line-listing, such as for different dosage forms or indications, if such differentiation facilitates
presentation and interpretation of the data.
5.3.7.b.
An aggregate summary for each of the line-listings should usually be presented. These tabulations
usually contain more terms than patients.
It would be useful to have separate tabulations (or columns) for serious reactions and for nonserious reactions, for listed and unlisted reactions; other breakdowns might also be appropriate
(e.g. by source of report). See Annex 5.2.1. Table 3, for a sample data presentation on serious
reactions.
Data on serious reactions from other sources (see Chapter I.5, Section 2.6.a) should normally be
presented as a summary tabulation. If useful, the tabulations may, for example, be sorted by source
of information or country.
When the number of cases is very small, or the information inadequate for any of the tabulations, a
narrative description rather than a formal table is considered suitable.
A tabulation of events in Medically Confirmed Cases by SOC. The terms used in these tables
should ordinarily be those used by the MAH to describe the case. Events should be sorted by
System Organ Class (SOC), then by Preferred Term (PT). Listedness in this tabulation is
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determined at the case level rather than at the event level. Therefore in some instances an event
may appear to be both listed and unlisted, depending on the other events present in the
respective case. Seriousness, however, is assessed at the event level (See Annex 5.2.1. Table
4).
A tabulation of events in Non-Medically Confirmed Cases by SOC. Events should be sorted
by System Organ Class (SOC), then by Preferred Term (PT). (See Annex 5.2.1. Table 5)
A Cumulative Summary of Serious and Unlisted Events As previously described, the data in
summary tabulations should be interval data, as should the line-listings from which they are
derived. However, for ADRs that are both serious and unlisted, a cumulative figure (i.e., all
cases reported to date) should be provided in the table(s) or as a narrative. (See Annex 5.2.1.
Table 6)
5.3.7.c.
This section may be used for brief comments on the data concerning individual cases. For
example, discussion may be presented on particular serious or unanticipated findings (their nature,
medical significance, mechanism, reporting frequency, etc.). The focus here should be on
individual case discussion and should not be confused with the global assessment in the PSUR
section Overall Safety Evaluation (see Chapter I.5, Section 3.10).
5.3.8. PSUR section Studies
All studies (non-clinical, clinical and epidemiological) yielding safety information (this includes
lack of efficacy data) with a potential impact on product information, studies specifically planned,
in progress and those published that address safety concerns should be included with a discussion
of any interim or final results. The MAH should not routinely catalogue or describe all the studies.
Studies that are part of the Risk Management Plan should be mentioned (see Chapter I.5, Section
3.9.c).
5.3.8.a.
All relevant studies containing important safety information and newly analyzed during the
reporting period should be described, including those from epidemiological, toxicological or
laboratory investigations. Reference should be made to the Risk Management Plan, where
applicable. The study design and results should be clearly and concisely presented with attention to
the usual standards of data analysis and description that are applied to non-clinical and clinical
study reports.
Copies of full study reports should be appended, e.g. in case of post-authorization safety studies
and for other studies with a significant safety finding only if deemed appropriate.
The newly analyzed PASS in this reporting period should be appended with all its related
documents & reports.
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5.3.8.b.
New studies specifically planned or conducted to examine a safety concern (actual or hypothetical)
should be described (e.g. objective, starting date, projected completion date, number of subjects,
protocol abstract).
When possible and relevant, if an interim analysis was part of the study plan, the interim results of
ongoing studies may be presented. When the study is completed and analyzed, the final results
should be presented in a subsequent PSUR as described in Chapter I.5, Section 3.8.a.
Copies of full reports should be appended in the case of post-authorization safety studies and for
other studies with a significant safety finding only if deemed appropriate.
Planned studies should be discussed in the Risk Management Plan (see Chapter I.3) and if relevant
in the related PSUR section (see Chapter I.5, Section 3.9.c).
5.3.8.c.
Published Studies
Reports in the scientific and medical literature, including relevant published abstracts from
meetings, containing important safety findings (positive or negative) should be summarized and
publication reference(s) provided.
5.3.8.d.
Other Studies
The MAH should provide any relevant information from the data collected by pregnancy exposure
registries and a discussion of the positive and negative experience of use of the medical product
during pregnancy.
5.3.9. PSUR section Other information
5.3.9.a.
Efficacy-related Information
Late-breaking Information
Any important, new information received after the database was frozen for review and report
preparation may be presented in this section. Examples include significant new cases or important
follow-up data. These new data should be taken into account in the PSUR section Overall Safety
Evaluation (see Chapter I.5, Section 3.10).
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5.3.9.c.
When a specific Risk Management Plan is in place, it should be discussed. In this case, the status
of the Risk Management Plan and its amendments prior to the data lock point should be presented
together with all available study results.
The assessment of the effectiveness of the risk management system should be presented (see
Chapter I.3).
5.3.9.d.
When a more comprehensive safety or risk-benefit analysis (e.g. all indications reviewed) has been
conducted separately, a summary of the analysis should be included in this section.
5.3.10. PSUR section Overall Safety Evaluation
The MAH should provide a concise analysis of the data presented, taking into account any latebreaking information (see Chapter I.5, Section 3.9.b), and followed by the MAHs assessment of
the significance of the data collected during the period. Discussion and analysis of the Overall
Safety Evaluation should be organized by SOC rather than by listedness or seriousness; the latter
properties should still be covered under each SOC. Although related terms may be found in
different SOCs, they should be reviewed together for clinical relevance.
Standardized MedDRA Queries (SMQs) may be used for signal detection and the use of SMQs is
recommended in order to retrieve and review cases of interest where signals are identified from
adverse reaction databases.
The MAH should also review the cumulative experience and highlight any new information on:
This section should also explicitly address any new safety concern on the following (lack of
significant new information should be mentioned for each):
Interactions;
Experience with overdose, deliberate or accidental, and its treatment;
Abuse or misuse;
Positive or negative experiences during pregnancy or lactation;
Experience in special patient groups (e.g. children. elderly, organ impaired, a qualitative
description of off-label use should be given);
Effects of long-term treatment;
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Patient/Consumer and other non-healthcare professional reports (see Chapter I.5, Section 3.7),
if appropriate;
Prescription errors/medication errors, including those associated with invented names or with
the presentation of the medicinal products, that have safety implications, if available.
A subsection of the PSUR should deal with use of the medicinal product in children if the product
has a pediatric indication, if there is evidence of significant off-label use in children or if there are
adverse reactions reported in the pediatric population. Data from completed or ongoing clinical
trials should be presented separately from spontaneous reports (see Annex 3.1.3).
5.3.11. PSUR section Conclusion
The Conclusion should address the overall risk-benefit balance in the context of the data
presented in the PSUR and:
indicate which safety data are not in accordance with previous cumulative experience and the
reference safety information (CCSI);
specify and justify any action recommended or initiated.
The need to amend the SPC should be addressed in the cover letter from the MAH, where
consistency between the CCSI and the SPC is cross-checked and any comment or planned action is
proposed.
Having made a decision to amend the SPC, the MAH should submit a variation application at the
same time as the PSUR or, where this is not possible; state a proposed timetable for submission.
Introduction (a brief description of the purpose of the document specifying the time periods
covered and cross-referencing any appended PSURs);
Worldwide marketing authorization status (number of countries which have approved the
product);
Update on regulatory authority or MAH-initiated actions for safety reasons (an integrated
summary of actions taken if appropriate);
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In addition, the cover letter accompanying the Summary Bridging Report should also contain
information highlighting any significant differences between the approved SPC and the current
CCSI.
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Changes to the CCSI (including a copy of the most recent CCSI document if it differs from the
one in the PSUR);
Significant worldwide regulatory authorities actions relevant to safety;
Line-listing(s) and/or summary tabulations;
Conclusions (brief overview).
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throughout the PSUR, but the conclusion section states that there were no significant issues
relating to changes in the riskbenefit profile of the product.
Examples of non-compliance in the pharmacovigilance system with respect to PSUR preparation
may include:
1. There is no system to ensure that PSURs contain cases received prior to the current reporting
period, but for which significant follow-up information has been received within the current
reporting period. Cases where follow-up information is not considered to have any impact on
the overall assessment of the case, and has not led to relevant coding changes for the case, do
not need to be discussed in the body of the PSUR.
2. There is no mechanism in place to ensure that Competent Authority requests made at the time
of assessment of a PSUR are addressed in subsequent PSURs.
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protocol but falls within the current practice and the prescription of the medicine is clearly
separated from the decision to include the patient in the study. No additional diagnostic or
monitoring procedures shall be applied to the patients and epidemiological methods shall be used
for the analysis of the collected data.
In this context it is considered important to clarify that interviews, questionnaires and blood
samples may be considered as normal clinical practice. Based on these definitions a fundamental
distinction can be made between non-interventional (observational) and interventional post
authorization safety studies. The latter are considered clinical trials.
If the definition of non-interventional is not met, the study should be considered as interventional.
For instance, studies exploring the following after a product has been authorized, should be
considered as interventional:
new indications,
new routes of administration or
new combinations.
The guidance on Good Clinical Practice does not apply to non-interventional post-authorization
studies.
The guidance below relates principally to those non-interventional post-authorization studies
where there is a known safety issue under investigation and/or where the numbers of patients to be
included in the study will add significantly to the existing safety data for the product(s).
A safety concern may be unexpectedly identified in the course of performing a study on an
authorized medicinal product that would normally fall outside the scope of this guidance. In that
case, the MAH and specifically the QPPV are expected to inform EPVC immediately and to
provide a brief report on progress at intervals and at study end as requested by EPVC.
If there is doubt as to whether or not a study comes under the scope of the present guidance, the
company should discuss the intended protocol with EPVC (see Chapter I.6, Section 4.1).
In addition to the guidance below, MAHs should consider the Guidelines for Good
Pharmacoepidemiology Practices issued by the International Society for Pharmacoepidemiology
(ISPE) (1).
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Reports of all serious adverse reactions arising from such studies within Egypt, should be
reported on an expedited basis (i.e. within 15 calendar days), to EPVC. These reports should
also be included in the PSURs;
Reports of NON-serious adverse reactions arising from such studies within Egypt should be
reported to EPVC within 90 days. These reports should also be included in the PSURs;
Reports on all adverse reactions arising from such studies occurring outside Egypt should be
reported only on the Periodic Safety Update Reports (PSURs) in accordance with Chapter I.5
All adverse reactions/events arising from such studies occurring outside & inside Egypt
including those which are considered non-serious should be summarized in the final study
report in frequency tables.
MAHs should ensure that they are notified by the investigator of serious adverse reactions and, if
specified in the study protocol, of events (those not suspected by the investigator or the MAH to be
adverse reactions).
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In certain study designs, such as case-control or retrospective cohort studies (see Data Sources in
Table I.6.A), in which it is not feasible or appropriate to make an assessment of causality between
medical events recorded and the medicinal products at individual case level, expedited reporting of
Individual Case Safety Reports (ICSRs) is not required. In case of doubt, the MAH should clarify
the reporting requirements with EPVC.
6.4.3. Progress and Final Study Reports
a) Studies requested by EPVC
MAHs should provide a study progress report annually, or more frequently as requested by
EPVC (e.g. according to the Risk Management Plan milestones) or on their own initiative. If the
study is discontinued, a final report should also be submitted, which will include the reasons for
stopping the study.
The content of the progress report should follow a logical sequence and should include all the
available data which is judged relevant for the progress of the study; e.g. number of patients who
have entered the study according to their status (exposure, outcome, etc.), problems encountered
and deviations from the expected plan. After review of the report, EPVC may request additional
information.
A final study report should be submitted according to an agreed timetable (e.g. Risk Management
Plan milestones). For the content of the final report consideration should be given to the
recommendations laid down in Table I.6.C at the end of this Chapter. The findings of the study
should be made public, preferably through scientific journals.
Both progress and final reports should be sent to EPVC. For evaluation of such reports, the same
procedure as for evaluation of the protocol stated above (see Chapter I.6, Section 4.1) should be
followed.
b) Studies performed at MAH's initiative
Progress and final reports should be included or updated in the corresponding PSUR and/or Risk
Management Plan. When a safety concern is raised, a report should be submitted immediately to
EPVC. The findings of the study should be made public, preferably through scientific journals.
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There are a number of observational study designs that are useful in validating signals from
spontaneous reports or case series. Major types of these designs are cross-sectional studies,
case control studies, and cohort studies (both retrospective and prospective).
1.2.1 Cross-sectional Study (Survey)
Data collected on a population of patients at a single point in time (or interval of time)
regardless of exposure or disease status constitute a cross-sectional study. These types of
studies are primarily used to gather data for surveys or for ecological analyses.
The major drawback of cross-sectional studies is that the temporal relationship between
exposure and outcome cannot be directly addressed, which limits its use for aetiologic
research unless the exposures do not change over time. These studies are best used to examine
the prevalence of a disease at one time-point or to examine trends over time, when data for
serial time-points can be captured. These studies may also be used to examine the crude
association between exposure and outcome in ecologic analyses.
1.2.2 Cohort Study
In a cohort study, a population-at-risk for an event of interest is followed over time for the
occurrence of that event. Information on exposure status is known throughout the follow-up
period for each patient. A patient might be exposed to a medicinal product at one time during
follow-up, but non-exposed at another time point. Since the population exposure during
follow-up is known, incidence rates can be calculated. In many cohort studies involving
exposure to medicinal product(s), comparison cohorts of interest are selected on the basis of
medication use and followed over time. Cohort studies are useful when there is a need to
know the incidence rates of adverse events in addition to the relative risks of adverse events.
Multiple adverse events may also be investigated using the same data source in a cohort
study. However, it may be difficult to recruit sufficient numbers of patients who are exposed
to a product of interest (such as an orphan drug) or to study very rare outcomes. The
identification of patients for cohort studies may come from large automated databases or from
data collected specifically for the study at hand. In addition, cohort studies may be used to
examine safety concerns in special populations (the elderly, children, patients with co-morbid
conditions, pregnant women) through oversampling of these patients or by stratifying the
cohort if sufficient numbers of patients exist.
Cohort studies may be prospective or retrospective depending on when the outcome of
interest occurs in relation to the commencement of the research: If the outcome occurs after
the research begins, it would be prospective; if the outcome had already occurred when the
investigation began, it would be retrospective.
1.2.3 Case-control Study
In a case-control study, cases of disease (or events) are identified. Controls, or patients
without the disease or event of interest, are then selected from the source population that gave
rise to the cases.
The controls should be selected in such a way that the prevalence of exposure to the
medicinal product among the controls represents the prevalence of exposure in the source
population. The exposure status of the two groups is then compared using the odds ratio,
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which is an estimate of the relative risk of disease among the exposed as compared to the nonexposed. Patients may be identified from an existing database or using data collected
specifically for the purpose of the study of interest. If safety information is sought for special
populations, the cases and controls may be stratified according to the population of interest
(the elderly, children, pregnant women, etc.). For rare adverse events, existing large
population-based databases are a useful and efficient means of providing needed exposure
and medical outcome data in a relatively short period of time. Case control studies are
particularly useful when the goal is to investigate whether there is an association between a
medicinal product (or products) and one specific rare adverse event, as well as to identify risk
factors for adverse events (or actually, effect-modifiers). Risk factors may include conditions
such as renal and hepatic dysfunction, which might modify the relationship between the drug
exposure and the adverse event. Under specific conditions, a case-control study may also
provide the absolute incidence rate of the event. If all cases of interest (or a well-defined
fraction of cases) in the catchment area are captured and the fraction of controls from the
source population is known, an incidence rate can be calculated.
As in cohort studies, case-control studies may be prospective or retrospective (see 1.2.2. of
this Table). When the source population within which the case-control study is conducted is a
well-defined cohort, it is then possible to select a random sample from it to form the control
series. The name nested case-control study has been coined to designate those studies in
which the control sampling is density-based (e.g. the control series represents the person-time
distribution of exposure in the source population). The case-cohort is also a variant in which
the control sampling is performed on those persons who make up the source population
regardless of the duration of time they may have contributed to it.
A case-control approach could also be set up as a permanent scheme to identify and quantify
risks (case-control surveillance). This strategy has been followed for rare diseases with a
relevant aetiology fraction attributed to medicinal products, including blood dyscrasias or
serious skin disorders.
1.2.4 Other Novel Designs
Some novel designs have been described to assess the association between intermittent
exposures and short-term events, including the case-series (10), the case-crossover (11) and
the case-time control studies. In these designs only cases are used and the control information
is obtained from past person-time experience of the cases themselves. One of the important
strengths of these designs is that those confounding variables that do not change within
individuals are automatically matched.
1.3 Clinical Trials
When significant risks are identified from pre-approval clinical trials, further clinical studies
might be called for to evaluate the mechanism of action for the adverse reaction. In some
instances, pharmacodynamic and pharmacokinetic studies might be conducted to determine
whether a particular dosing instruction can put patients at an increased risk of adverse events.
Genetic testing may also provide clues about which group of patients might be at an increased
risk of adverse reactions. Furthermore, based on the pharmacological properties and the
expected use of the medicinal product in general practice, conducting specific studies to
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investigate potential drug-drug interactions and food-drug interactions might be called for.
These studies may include population pharmacokinetic studies and drug concentration
monitoring in patients and normal volunteers. Sometimes, potential risks or unforeseen
benefits in special populations might be identified from pre-approval clinical trials, but cannot
be fully quantified due to small sample sizes or the exclusion of subpopulations of patients
from these clinical studies. These populations might include the elderly, children, or patients
with renal or hepatic disorder. Children, the elderly, and patients with co-morbid conditions
might metabolize medicinal products differently than patients typically enrolled in clinical
trials. Further clinical trials might be used to determine and to quantify the magnitude of the
risk (or benefit) in such populations. In performing clinical trials, national legislative
requirements or guidelines should be followed where these exist.
1.3.1 Large Simple Trials
A Large Simple Trial is a specific form of clinical trial where large numbers of patients are
randomized to treatment but data collection and monitoring is kept to the absolute minimum
consistent with the aims of the study. This design is best used in pharmacovigilance to
elucidate the risk-benefit profile of a medicinal product outside of the formal/traditional
clinical trial setting and/or to fully quantify the risk of a critical but relatively rare adverse
event. These studies qualify as clinical trials and are subject to national legislative
requirements or guidelines where these exist.
1.4 Other Studies
Descriptive studies are an important component of pharmacovigilance, although not for the
detection or verification of adverse events associated with exposures to medicinal products.
These studies are primarily used to obtain the background rate of outcome events and/or
establish the prevalence of the use of medicinal products in specified populations.
1.4.1 Occurrence of Disease
The science of epidemiology originally focused on the natural history of disease, including
the characteristics of diseased patients and the distribution of disease in selected populations,
as well as estimating the incidence and prevalence of potential outcomes of interest. These
outcomes of interest now include a description of disease treatment patterns and adverse
events. Studies that examine specific aspects of adverse events, such as the background
incidence rate of or risk factors for the adverse event of interest, may be used to assist in
putting spontaneous reports into perspective. For example, an epidemiologic study can be
conducted using a disease registry to understand the frequency at which the event of interest
might occur in specific subgroups, such as patients with concomitant illnesses.
1.4.2 Drug Utilization Study
Drug utilization studies (DUS) describe how a medicinal product is marketed, prescribed and
used in a population, and how these factors influence outcomes, including clinical, social, and
economic outcomes. These studies provide data on specific populations, such as the elderly,
children, or patients with hepatic or renal dysfunction, often stratified by age, gender,
concomitant medication and other characteristics. DUS may be used to determine if a product
is being used in these populations. From these studies, denominator data may be derived for
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use in determining rates of adverse reactions. DUS have been used to describe the effect of
regulatory actions and media attention on the use of medicinal products, as well as to develop
estimates of the economic burden of adverse reactions. DUS may be used to examine the
relationship between recommended and actual clinical practice. These studies may help to
determine whether a medicinal product has potential for abuse by examining whether patients
are taking escalating dose regimens or whether there is evidence of inappropriate repeat
prescribing. Important limitations of these studies may include a lack of clinical outcome data
or information of the indication for use of a product.
2 Data Sources
Pharmacoepidemiological studies may be performed using a variety of data sources.
Traditionally, field studies were required for retrieving the necessary data on exposure,
outcomes, potential confounders and other variables, through interview of appropriate
subjects (e.g. patients, relatives) or by consulting the paper-based medical records. However,
the advent of automated healthcare databases has remarkably increased the efficiency of
pharmacoepidemiologic research.
There are two main types of automated databases, those that contain comprehensive medical
information, including prescriptions, diagnosis, referral letters and discharge reports, and
those mainly created for administrative purposes, which require a record-linkage between
pharmacy claims and medical claims databases. These datasets may include millions of
patients and allow for large studies. They may not have the detailed and accurate information
needed for some research, such as validated diagnostic information or laboratory data, and
paper-based medical records should be consulted to ascertain and validate test results and
medical diagnoses.
Depending on the outcome of interest, the validation may require either a case-by-case
approach or just the review of a random sample of cases. Other key aspects may require
validation where appropriate. There are many databases in place for potential use in
pharmacoepidemiological studies or in their validation phase. MAHs should select the best
data source according to validity (e.g. completeness of relevant information, possibility of
outcome validation) and efficiency criteria (e.g. time span to provide results). External
validity should also be taken into account: As far as feasible the data source chosen to
perform the study should include the population in which the safety concern has been raised.
In case another population is involved, the MAH should evaluate the differences that may
exist in the relevant variables (e.g. age, sex, pattern of use of the medicinal product) and the
potential impact on the results. In the statistical analysis, the potential effect of modification
of such variables should be explored.
With any data source used, the privacy and confidentiality regulations that apply to personal
data should be followed.
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The names, titles, degrees, addresses and affiliations of all responsible parties, including
the principal investigator, co-investigators and a list of all collaborating primary institutions
and other relevant study sites
A critical review of the literature to evaluate pertinent information and gaps in knowledge
The literature review should describe specific gaps in knowledge that the study is intended
to fill. The literature review might encompass relevant animal and human experiments,
clinical studies, vital statistics and previous epidemiologic studies. The literature review
should also cite the findings of similar studies and the expected contribution of the current
study.
1. The overall research design, strategy and reasons for choosing the proposed
study design.
Research designs include case-control, cohort, cross-sectional, nested case-control or
hybrid designs.
3. The strategies and data sources for determining exposures, health outcomes and
all other variables relevant to the study objectives, such as potential
confounding variables and effect modifiers, using validated measurements
whenever possible
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5. Projected study size, statistical precision and the basis for their determination
Describe the relation between the specific aims of the study and the projected study size
in relation to each outcome.
9. A description of quality assurance and quality control procedures for all phases
of the study
Mechanisms to ensure data quality and integrity should be described, including,
abstraction of original documents. As appropriate, include certification and/or
qualifications of any supporting laboratory or research groups.
10. Limitations of the study design, data sources and analytic methods
At a minimum, issues relating to confounding, misclassification, selection,
generalizability and random error should be considered. The likely success of efforts
taken to reduce errors should be discussed.
I
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This section should include information about whether study subjects will be placed at risk
as a result of the study, provisions for maintaining confidentiality of information on study
subjects and potential circumstances and safeguards under which identifiable personal
information may be provided to entities outside the study. Conditions under which the study
would be terminated (stopping rules) should be described. Procedures for monitoring
results should be described; for prospective studies consider using a Data Safety
Monitoring Board (DSMB) for this purpose.
J
A description of plans for disseminating and communicating study results, including the
presence or absence of any restrictions on the extent and timing of publication
There is an ethical obligation to disseminate findings of potential scientific or public health
importance (e.g. results pertaining to the safety of a marketed medicinal product).
Bibliographic references
Annexes
For any additional or complementary information on specific aspects not addressed in the
body text (e.g. questionnaires, case report forms).
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An abstract
The names, titles, degrees, addresses and affiliations of the principal investigator and all
co-investigators
A description of circumstances that may have affected the quality or integrity of the data
Describe the limitations of study approach and the methods used to address them (e.g.
response rates, missing or incomplete data).
10
11
12
13
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7.
Overall Pharmacovigilance
Regulatory Action
Evaluation
and
Safety-Related
7.1. Introduction
Granting of a marketing authorization for a medicinal product indicates that it is considered to
have a satisfactory risk-benefit balance under the conditions defined in the Summary of Product
Characteristics (SPC) and in accordance with the Risk Management Plan (where applicable) (see
Chapter I.3), on the basis of the information available at that time.
During the post-authorization period, larger and more diverse populations than those during the
development phase of the product are likely to be exposed. New information on the benefits and
risks of the product will be generated, and evaluation of this information and any safety concerns
should be an on-going process, both by the MAH and EPVC.
Both the MAH and EPVC must keep abreast of all relevant information in order to fulfill the
following responsibilities:
Ensuring that all sources of information are screened regularly to identify any potential signals;
Ensuring that appropriate action is taken in response to new evidence which impacts on the
known risk-benefit balance;
Keeping EPVC, Healthcare Professionals and Patients informed.
This Chapter
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The responsibilities of the MAH, and in particular of the QPPV, are provided in Chapter I.1,
Section 4. It is the responsibility of the QPPV to provide EPVC with any information relevant to
the evaluation of benefits and risks afforded by a medicinal product, including appropriate
information on post-authorization safety studies.
The MAH should immediately inform EPVC of any prohibition or restriction imposed by the
Competent/regulatory authorities of any country in the world in which the medicinal product is
marketed and of any other new information which might influence the evaluation of the benefits
and risks of the medicinal product.
The MAH and EPVC should agree on the appropriate scope and timelines for evaluation and
agreed responsibilities for review. The MAH should provide a comprehensive evaluation of the
issue and the risks in the context of the benefits at the earliest opportunity and no later than the
agreed date specified in the written communications between the Competent Authority and the
MAH.
the extent to which the medicinal product cures or improves the underlying condition or
relieves the symptoms;
the response rate and duration and quality of life.
In the case of prophylactic medicinal products, the benefit may be considered as the reduction
of the expected severity or incidence of the disease.
With diagnostics, the benefit will be defined in terms of sensitivity and specificity or, in other
words, false negative and false positive rates.
Any available information on misuse of the product and on the level of compliance in clinical
practice, which may have an impact on the evaluation of its benefits, should also be considered.
The quality and degree of the evidence of benefit should be taken into account. Benefit should, as
far as possible, be expressed in quantitative terms in a way that makes it comparable to the risks.
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Important issues, which should be addressed in the assessment of adverse reactions, include
evidence of causal association, seriousness, absolute and relative frequency and presence of risk
factors, which may allow preventive measures.
The quality and degree of evidence of risk should be taken into account. In the assessment of risks
and consideration of regulatory action, it is important to note that rarely even a single case report
may establish a causal association with the suspected medicinal product and impact on the riskbenefit balance. Risk assessment should also take account of the potential for overdose, misuse,
abuse, off-label use and medication errors.
When new safety concerns are identified, which, could have an impact on the overall risk-benefit
balance of a medicinal product, the MAH should propose appropriate studies to further investigate
the nature and frequency of the adverse reactions. A new or updated Risk Management Plan
should be proposed accordingly (see Chapter I.3). The studies should comply with the guidance
provided in Chapter I.6.
7.3.3. Risk-Benefit Assessment
Whenever possible, both benefits and risks should be considered in absolute terms and in
comparison to alternative treatments. The magnitude of risk that may be considered acceptable is
dependent on the seriousness of disease being treated and on the efficacy of the medicinal product.
For example:
In the treatment of a disease with high mortality, a high risk of serious adverse reactions may
be acceptable providing the benefits associated with treatment have been shown to be greater.
For medicines used in chronic diseases or in prevention of disabling diseases, some level of
risk may be acceptable if there is a substantial improvement in the prognosis or quality of life.
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In situations where the main benefit is symptom relief for minor illnesses in otherwise healthy
individuals or where individuals are treated not only for their own benefit but also for the
benefit of the community (e.g. vaccination), risk levels must be extremely low.
In cases where therapeutic benefit is limited, even a few cases of a serious adverse reaction
may suffice to render the risk-benefit balance as unfavorable.
If, for two medicinal products with essentially similar efficacy and types of adverse reactions,
one or more serious adverse reactions were shown to differ in frequency, the risk-benefit
balance of the product with the higher adverse reaction frequency may no longer be acceptable.
The populations being treated must also be taken into account, as should off-label use.
If there are important new safety concerns requiring urgent action, the MAH, should initiate an
urgent safety restriction (USR) followed by variation. These measures should be immediately
communicated to CAPA. If no objections are raised within 24 hours after receipt of an application,
the USR may be introduced and the corresponding application for the variation should be
submitted without delay to CAPA.
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7.6. Communication
In the event of a product withdrawal, an urgent safety restriction or an important variation, the
content of Public Statements, Direct Healthcare Professional Communication (DHPC) and other
communication from the MAH to Healthcare Professionals, Patients and the general public,
including the time frame for the distribution of such communication, should be agreed with EPVC.
MAHs are reminded of their legal obligations not to communicate information relating to
pharmacovigilance concerns to the public without notification to EPVC. For further guidance see
Part II.
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PART II
Guidelines for Marketing Authorization Holders and
the Egyptian Pharmacovigilance Center (EPVC)
Communication
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Provision of information about the safe and effective use of medicinal products supports
appropriate use and should be considered as a public health responsibility.
Communication of such information needs to be considered throughout the risk management
process (see Chapter I.3).
It is essential that such information is communicated to Healthcare Professionals and relevant
partners including Patient and Healthcare Professional organizations, societies and
pharmaceutical wholesalers.
In principle, significant new or emerging information should be brought to the attention of
Healthcare Professionals before the general public, in order to enable them to take action and
respond to Patients adequately and promptly. The important function of Healthcare
Professionals in disseminating such information to Patients and the general public is
recognized and should be supported.
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The overriding principle should be to ensure that the right message is delivered to the right
persons at the right time.
Effective communication on safe and effective use of medicinal products authorized in Egypt
entails:
co-operation of all partners;
co-ordination between relevant partners, within and, if possible, outside Egypt; and
a strategy which meets the requirements resulting from the urgency to communicate
and the expected public health impact of the information.
A DHPC should not usually be distributed before the corresponding regulatory procedure has
been completed, however, exceptionally (e.g. in the case of an urgent safety restriction) there
may be a need to disseminate a DHPC prior to completion of a procedure.
In general, an agreement between the MAH and EPVC is needed on the format and content of
the information, recipients and the timetable. The agreed timetable for release of the
information should be fully respected by all partners.
A change in the outcome of the evaluation of the risk-benefit balance due to:
o new data, in particular from a study or spontaneous reports that identify a previously
unknown risk or a change in the frequency or severity of a known risk; or
o new data on risk factors and/or on how adverse reactions may be prevented; or
o substantiated knowledge that the medicinal product is not as effective as previously
considered ; or
o evidence that the risks of a particular product are greater than those of alternatives with
similar efficacy;
or
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A DHPC should not be used to provide safety information which does not require urgent
communication or is otherwise important to be communicated to Healthcare Professionals at
individual level, such as changes to the SPC which do not impact on the conditions of appropriate
use of the medicinal product.
1.5. Key Principles for Preparation of Texts for Direct Healthcare Professional
Communications
When drafting a DHPC, the Template (see Annex 5.3.1) and the guidance provided there should be
followed as appropriate, together with the principles described below:
The message of the DHPC should be clear and concise with regard to the safety concern. It
should not exceed two pages.
The reason for dissemination of a DHPC at a particular point in time should be explained.
The safety concern should be placed in the context of the overall benefit of the treatment and
not be presented as stand-alone information.
The MAH should ensure that pharmacovigilance information to the general public (this
includes Healthcare Professionals) is presented objectively and is not misleading.
In general, the texts of DHPCs should be reviewed by, or if the timetable allows, tested among
representatives of the target groups of Healthcare Professionals in order to assess clarity and
understanding of the risk and expected adherence to the recommendations provided in the
DHPC. Alternatively, standard phrases may be tested and subsequently used, as appropriate,
particularly in urgent situations.
In order to allow Healthcare Professionals to prepare responses to questions from Patients, the
DHPC should also include the content of any information communicated directly to the general
public. In case of suspension, withdrawal or revocation of a marketing authorization, the
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DHPC should detail the type and procedure of recall of the medicinal product(s) from the
market (e.g. pharmacy or patient level, date of recall).
Public communication of the safety information issued to any target population by other
Competent Authorities and other public bodies, ideally within and outside Egypt, should be
taken into account.
The DHPC should include a reminder of the need to report suspected adverse reactions in
accordance with national spontaneous reporting systems.
The estimated time schedule for follow-up action, if any, by CAPA/ EPVC or the MAH should
be provided.
A list of contact points for further information, including website address (es), telephone
numbers and a postal address to write to, should be provided at the end of the DHPC.
The DHPC may include a statement indicating that the DHPC has been agreed with CAPA/
EPVC.
the proposed texts of any related communication documents (see Chapter II.1, Section 6.2.
(2)).
The timing of the submission should allow EPVC reasonable time (a minimum of two working
days) to comment on the Communication Plan and the proposed communication texts prior to their
finalization. Exceptionally, less than two working days may be acceptable in the case of some
urgent safety restrictions. The MAH should take into account comments from EPVC and discuss
any outstanding issues when finalizing these proposals. Ideally, the MAH should closely cooperate
with EPVC to finalize the text of the DHPC. The final Communication Plan and communication
texts should be submitted to EPVC.
1.6.2. Phased Approach to Processing
The processing of a DHPC consists of four phases:
1. Consideration phase: Initiation of the process
The process may be initiated by the MAH or EPVC.
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When the MAH considers that a DHPC may be necessary, EPVC should be contacted and the
documents required for the preparation of the DHPC submitted, as set out below. When EPVC
considers that a DHPC may be necessary, it is recommended that the EPVC sends a request letter
(in case of urgency the MAH may additionally be contacted by telephone and/or e-mail) requesting
preparation of a draft DHPC and a Communication Plan. This request letter should provide the
rationale for the request and the timetable for submission. When a request letter is received, the
MAH should designate a contact point within the company for liaison with EPVC.
If the MAH considers that a DHPC is not appropriate or requires additional clarification, a written
request may be submitted to EPVC.
There may be situations in which more than one MAH is involved in the dissemination of a
DHPC, e.g. where an interaction, a class-effect or generic medicinal products are concerned. In
such situations, the objective is to provide consistent information to Healthcare Professionals and
to avoid multiple DHPCs on the same safety concern from different MAHs which may lead to
confusion. Where the number of MAHs involved is limited to two or three, they should work
together to issue a single DHPC. For a larger number of MAHs or if a single joint DHPC is not
agreed, EPVC may opt to issue the DHPC.
2. Pre-communication phase: Preparation of a DHPC
Once the intention to disseminate a DHPC is confirmed, the MAH should submit a draft
Communication Plan including the following:
the draft DHPC and objective of the DHPC and other communication texts (including
amendments to the Product Information (SPC, Package Leaflet and Labeling), either
mentioned in the DHPC text or, preferably, appended to the draft DHPC, if the final revised
Product Information is available) as well as the key message to the public;
timelines for comments on the Communication Plan and draft communication texts by
EPVC;
timelines for agreement on final texts between the MAH and EPVC;
timelines for agreement on the date and time of release of the DHPC and information to
the general public.
any draft Communication Plans and communication texts under discussion with other
Competent Authorities (outside Egypt for authorized products).
a list of proposed recipients (target groups, e.g. general practitioners, specialists, coroners,
pharmacists, nurses; hospitals/ambulatory care/other institutions), if appropriate;
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a list of related communication documents, if appropriate, e.g. press release, questions &
answers document, patient information sheet, and a description of their dissemination
mechanisms in Egypt where the DHPC is planned to be disseminated;
a description of the strategy for the post-communication phase, including the evaluation of the
effectiveness of the DHPC, as outlined below in this Section.
an outline of proposed follow-up action and a draft Letter of Undertaking from the MAH on
further investigations, if applicable; and
The submitted documents should be in the form of 2 full original copies, after approval by EPVC,
the MAH will receive back 1 full original stamped copy, while the other will be retained at EPVC.
The proposed time and date for distribution should be considered carefully, with dissemination of a
DHPC at the beginning of a week considered ideal; however the release of urgent information
should not be delayed for this reason.
When defining the target groups of recipients, it should be recognized that it is not only important
to communicate with those Healthcare Professionals who will be able or likely to prescribe or
administer the medicinal product, but also to those who may diagnose adverse reactions, e.g.
emergency units, poison centres, or to appropriate specialists, e.g. cardiologists. It is also important
to consider provision of DHPCs to relevant pharmacists who serve as information providers within
healthcare systems and provide assistance and information to Patients, Healthcare Professionals,
including hospital wards and poison centres, as well as the general public, in particular where
media interest has arisen. The national professional associations of physicians, nurses and
pharmacists should systematically receive DHPCs for further dissemination of the information to
their members beyond the primary target groups of recipients.
DHPCs should contain an identification such as specific identifiers on the envelope (e.g. prominent
red box warning) or use of a specific colour of notepaper. The use of such specific identifiers is
encouraged to facilitate identification and focus Healthcare Professionals attention.
3. Communication phase: Dissemination of the DHPC
Implementation of the communication phase should adhere to the Communication Plan agreed
between the MAH and EPVC and should be accompanied by close monitoring of events by all
partners. Any significant event or problem occurring during the communication phase should be
communicated immediately between all relevant partners. If this reveals a need to change the
Communication Plan or a need for further communication to Healthcare Professionals, this should
be agreed between the MAH and EPVC.
4. Post-communication phase: Follow-up of the DHPC
After dissemination of a DHPC, a closing review should be performed by the MAH, identifying
any event or problem occurring during the communication phase requiring a change to the
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Communication Plan, any non-adherence to the Communication Plan as well as any difficulties
experienced during any of the above phases. Such difficulties may relate e.g. to the list of
recipients or the date and mechanism of dissemination. EPVC should be informed of the outcome
of this closing review and should also inform the MAH of difficulties they identified. If EPVC is
not satisfied, a written request should be made to the MAH to correct the situation. On the basis of
this information, action should be taken to prevent or anticipate similar problems in the future. All
partners should also perform internal reviews of their performance as part of integrated quality
management and take appropriate action for improvement as needed. In general, evaluation of the
public health impact and the effectiveness of DHPCs should be performed in order to evaluate if
the DHPCs have been received in a timely manner (check in a small sample of the target
population) and if the recommendations and key messages have been understood and followed
(e.g. by means of healthcare professional surveys or other study designs). This evaluation should
be performed by the Marketing Authorization Holder and is specifically relevant where DHPCs are
part of risk minimization activities in accordance with the applicable Risk Management Plan.
1.6.3. Translations
For authorized products, the proposed communication texts will be submitted in English as
working language.
Once the communication texts are agreed with EPVC, the MAH may prepare translations of the
DHPC in Arabic language only if requested by EPVC.
The draft translations should be submitted to EPVC for a language review within a reasonable time
(minimum of one working day). The MAH should take account of comments from EPVD and
discuss any outstanding issues when finalizing translations.
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ANNEXES
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ANNEX (1)
1. Glossary
1.1. General
Abuse of a medicinal product, synonym: Drug abuse
Persistent or sporadic, intentional excessive use of medicinal products which is accompanied by
harmful physical or psychological effects.
Adverse event (AE), synonym: Adverse experience
Any untoward medical occurrence in a patient or clinical-trial subject administered a medicinal product
and which does not necessarily have to have a causal relationship with this treatment. An adverse event
can therefore be any unfavorable and unintended sign (e.g. an abnormal laboratory finding), symptom,
or disease temporally associated with the use of a medicinal product, whether or not considered related
to the medicinal product.
Adverse reaction, synonym: Adverse drug reaction (ADR), Suspected adverse (drug) reaction
A response to a medicinal product which is noxious and unintended and which occurs at doses
normally used in man for the prophylaxis, diagnosis or therapy of disease or for the restoration,
correction or modification of physiological function.
Response in this context means that a causal relationship between a medicinal product and an adverse
event is at least a reasonable possibility (see ICH-E2A see Annex 4).
Adverse reaction also includes adverse clinical consequences associated with use of the product outside
the terms of the Summary of Product Characteristics or other conditions laid down for the marketing
and use of the product (including prescribed doses higher than those recommended, overdoses or
abuse).
See also under Adverse event, Serious adverse reaction, Unexpected adverse reaction, Listed adverse
reaction, Reportable adverse reaction, Unlisted adverse reaction
Clinical trial
Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or
other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify
any adverse reactions to one or more investigational medicinal product(s) and/or to study absorption,
distribution, metabolism and excretion of one or more investigational medicinal product(s) with the
objective of ascertaining its (their) safety and/or efficacy; This includes clinical trials carried out in
either one site or multiple sites.
An investigational medicinal product is a pharmaceutical form of an active substance or placebo being
tested or used as a reference in a clinical trial, including products already with a marketing
authorization but used or assembled (formulated or packaged) in a way different from the authorized
form, or when used for an unauthorized indication, or when used to gain further information about the
authorized form.
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Consumer
A person who is not a Healthcare Professional such as a Patient, lawyer, friend or
relative/parents/children of a Patient.
Company Core Data Sheet (CCDS)
A document prepared by the MAH containing, in addition to safety information, material relating to
indications, dosing, pharmacology and other information concerning the product.
Company Core Safety Information (CCSI)
All relevant safety information contained in the company core data sheet prepared by the MAH and
which the MAH requires to be listed in all countries where the company markets the product, except
when the local regulatory authority specifically requires a modification. It is the reference information
by which listed and unlisted are determined for the purpose of periodic reporting for marketed
products, but not by which expected and unexpected are determined for expedited reporting.
Data lock point
The date designated as the cut-off date for data to be included in a Periodic Safety Update Report.
Drug abuse
See under Abuse
Healthcare Professional
For the purposes of reporting suspected adverse reactions, Healthcare Professionals are defined as
medically qualified persons, such as physicians, dentists, pharmacists, nurses and coroners.
Individual Case Safety Report (ICSR), synonym: Safety report
A document providing the most complete information related to an individual case at a certain point of
time. An individual case is the information provided by a primary source to describe suspected adverse
reaction(s) related to the administration of one or more medicinal products to an individual Patient at a
particular point of time.
International Birth Date (IBD)
The date of the first marketing authorization for a medicinal product granted to the MAH in any
country in the world. For a medicinal product for which the International Birth Date is not known, the
MAH can designate an International Birth Date to allow synchronization of submission of Periodic
Safety Update Reports.
Invented name
The name of a medicinal product as it appears in the Product Information, or the common or scientific
name together with a trademark or the name of the MAH followed by the strength and the
pharmaceutical form of the product.
The common name is the International Non-proprietary Name (INN) recommended by the World
Health Organization, or if one does not exist, the usual common name.
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Non-clinical safety concerns that have not been observed or resolved in clinical studies
Adverse events observed in clinical trials or epidemiological studies for which the magnitude
of the difference, compared with the comparator group (placebo or active substance, or
unexposed group), on the parameter of interest raises a suspicion of, but is not large enough to
suggest, a causal relationship
A signal arising from a spontaneous adverse reaction reporting system
An event which is known to be associated with other products of the same class or which could
be expected to occur based on the properties of the medicinal product.
January 2012
A risk management system shall comprise a set of pharmacovigilance activities and interventions designed
to identify, characterize, prevent or minimize risks relating to medicinal products, including the assessment
of the effectiveness of those interventions.
Risk minimization
This is a set of activities used to reduce the probability of an adverse reaction occurring or its severity
should it occur.
Routine pharmacovigilance
Pharmacovigilance activities that should be conducted for all medicinal products.
Routine risk minimization activities
The warnings and information contained within the Summary of Product Characteristics and Patient
Leaflet, and the careful use of labeling and packaging, which aim to reduce the probability of an adverse
reaction occurring or its severity should it occur.
Safety concern
An important identified risk, important potential risk or important missing information.
Target Population
The Patients who might be treated by the medicinal product according to the indication(s) and
contraindication(s) in the Summary of Product Characteristics.
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ANNEX (2)
2. Abbreviations
ADR
AE
Adverse event
ATC
Anatomical-Therapeutic-Chemical Classification
CAPA
CCDS
CCSI
CHMP
CV(s)
DHPC(s) commonly
called DDL(s)
DUS
EBD
EDA
EDI
EEA
EMEA
EPVC
FDA
HBD
IBD
ICH
ICSR(s)
INN
IMP
IT
Information Technology
ISEP
LLTs
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LSR
MAH(s)
MedDRA
MPR
NUI
Non-Urgent Information
NPC
PASS
PhVWP
PL
Package Leaflet
PSUR(s)
QPPV
SOCs
SPC
SUSARs
USR
WHO
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ANNEX (3)
3. Other Guidelines and Relevant Terminology
3.1. Other Pharmacovigilance Guidelines
3.1.1. Note for Guidance on the Electronic Data Interchange (EDI) of Individual Case Safety
Reports (ICSRs) and Medicinal Product Reports (MPRs) in Pharmacovigilance During the
Pre- and Post- Authorization Phase in the European Economic Area (EEA)
Adopted at Community level in September 2004.
This Guideline is published under document reference number EMEA/115735/2004 on the EudraVigilance
website www.eudravigilance.emea.europa.eu.
3.1.2. Guideline on the Exposure to Medicinal Products During Pregnancy: Need for PostAuthorization Data
This Guideline (EMEA/CHMP/313666/2005) is available on the EMEA website http://www.emea.europa.eu.
3.1.3. Guideline on the Conduct of Pharmacovigilance for Medicines Used by the Paediatric
Population
This
Guideline
(EMEA/CHMP/PhVWP/235910/2005)
is
available
on
the
EMEA
website
http://www.emea.europa.eu.
3.2.2. Standard Terms on Pharmaceutical Dosage Forms, Routes of Administration and Containers
These Standard Terms are published by the Council of Europe and are available on the website of the European
Pharmacopoeia http://www.pheur.org.
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ANNEX (4)
4. ICH Guidelines
4.1. ICH-E2B(M) - Maintenance of the Clinical Safety Data Management Including: Data
Elements for Transmission of Individual Case Safety Reports
This Guideline is published under document reference number CPMP/ICH/287/95 modification corr. on the
EMEA website www.emea.europa.eu.
4.1.1. ICH- E2B Q&As (R5): Questions and Answers Data Elements for Transmission of Individual
Case Safety Reports
This Guideline is published under document reference number CPMP/ICH/3943/03 on the EMEA website
www.emea.europa.eu.
4.2. ICH-E2C(R1): Clinical Safety Data Management Periodic Safety Update Reports for
Marketed Drugs including Addendum to ICH-E2C
This Guideline is published under document reference number CPMP/ICH/288/95 for ICH-E2C and
CPMP/ICH/4679/02 for ICH-E2C Addendum on the EMEA website www.emea.europa.eu as a combined
document.
4.3. ICH-E2D: Post-Approval Safety Data Management - Definitions and Standards for
Expedited Reporting
This Guideline is published under document reference number CPMP/ICH/3945/03 on the EMEA website
www.emea.europa.eu.
152
January 2012
4.6. ICH-M2: Electronic Standards for Transmission of Regulatory Information (ESTRI) Individual Case Safety Report (ICSR)
Reference to the recommendations can be found on the EMEA website www.emea.europa.eu.
www.emea.europa.eu.
4.7.2. Units and Measurements Controlled Vocabulary
This Guideline is published under document reference number CHMP/ICH/175818/05 on the EMEA website
www.emea.europa.eu.
153
January 2012
ANNEX (5)
5. Templates
154
January 2012
1
2
3
4
5
6
Annex 1
Annex 2
Annex 3
Annex 4
Annex 5
Annex 6
Annex 7
Annex 8
Product information
Safety Specification
Pharmacovigilance Plan
Evaluation of the need for risk minimization activities
Risk Minimization Plan
Summary of the EG-RMP
Contact person details
Current (or proposed if initial EG-RMP) SPC, Package Leaflet
Synopsis of ongoing and completed clinical trial programme
Synopsis of ongoing and completed pharmacoepidemiological
study programme
Protocols for proposed and ongoing studies in pharmacovigilance
plan
Newly available study reports
Other supporting data
Details of proposed educational programme (if applicable)
The Egyptian display of RMP
To be valid an EG-RMP MUST contain sections 1, 2 & 3. With the exception of section 4
(which must be completed if additional risk minimization activities are proposed) all sections
should be provided. Annex 8 is required only in case of Medicinal products authorized for
Multinational MAH/Applicant.
Please ensure that the data provided in this document are coded in MedDRA terms where
appropriate and are consistent with those submitted electronically.
155
January 2012
dd/mm/yyyy
156
Version
January 2012
Table of contents
Part I
1.
Safety Specification
Non-clinical part of safety specification
Clinical part of safety specification
1.2.
1.3.
1.4.
1.5.
1.6.
Identified and potential interactions with other medicinal products, food and other
substances
1.7.
1.8.
1.9.
Pharmacovigilance Plan
2.1.
2.2.
2.3.
2.4.
2.5.
2.6.
Part II
3.
3.1.
3.2.
4.
5.
6.
ANNEXES
Annex 3: Ongoing & completed clinical trial programme
Annex 4: Pharmacoepidemiological programme
Annex 8: Egyptian Display of the RMP
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January 2012
Brief description of
product (chemical class,
mode of action etc.)
Indication(s)
Current if applicable
Proposed if applicable
Dosage
Pharmaceutical form(s)
and strength(s)
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PART I
1.
SAFETY SPECIFICATION
toxicity,
nephrotoxicity,
General safety pharmacology (cardiovascular [including QT interval prolongation,] nervous system, etc.)
Mechanisms for drug interactions
Other toxicity-related information or data
Safety Concern (From Non Clinical Studies)
1.1.2. <Specify need for additional non-clinical data if the product is to be used in special
populations>
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January 2012
1.2.1. Exposure
The following tables should be provided, separately for each indication with a summary table
showing total exposure. Provide each table, where available, based on exposed (to medicinal
product of interest) persons in:
a) randomized, blinded trial population only
b) all clinical trial populations (including open extension).
Table 1: BY DURATION
INDICATION (or TOTAL)
Duration of exposure
Cumulative Up to 1 m
Cumulative Up to 3 m
Cumulative Up to 6 m
Cumulative Up to 12 m
Table 2: BY DOSE
INDICATION (or TOTAL)
Dose of exposure
Dose level 1
Dose level 2
etc.
Persons
Person time
Persons
Person time
Persons
M
Person time
M
F
Age group 1
Age group 2
etx
Table 4: BY ETHNIC ORIGIN
INDICATION (or TOTAL)
Persons
Person time
Ethnic origin 1
Ethnic origin 2
etc.
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January 2012
Person time
Pregnant women
Lactating women
Renal impairment (specify or categorize)
Hepatic impairment (specify or categorize)
Cardiac impairment (specify or categorize)
Sub populations with genetic polymorphism
(specify)
Note the categories provided, are suggestions only and the tables should be tailored to the product,
clearly identified and justified. For example, for parenteral administration, consider number of
administrations e.g. 1, 2, 3 or more repeated exposures. For age and gender make explicit
reference to paediatric and elderly populations.
Population
studied
Duration
(study period)
Number of
persons (in each
group or of cases
and controls)
Study1
Study 2
etc.
Data on patients exposed post marketing should be provided based on market research where
possible. When the number of persons is calculated on the basis of sales data, details and
justification should be provided of the measure used to calculate exposure. Tables should be
provided for each indication where possible.
Table 1: BY AGE GROUP AND GENDER
Indication
Age group
Persons
M
Age group 1
Age group 2
etc.
Table 2: BY DOSE
Indication
Persons
Dose level 1
Dose level 2
etc.
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Table 3: BY COUNTRY
Indication
Persons
EU
Non-EU
Note the categories provided, are suggestions only and other relevant variables can be used e.g. oral versus
iv, duration of treatment etc.
1.3.
For each pivotal and supporting study, list exclusion criteria for studies.
Study
number
No of patients exposed
to this product in the
study
Age range
The limitations of the human safety database should be discussed in terms of the relevance of
inclusion and exclusion criteria and the populations actually studied in relation to the target
population(s). Where exclusion criteria are not proposed as contraindications to treatment this
should be discussed and justified. Populations to be considered for discussion should include (but
is not limited to):
-
Children
Elderly
Pregnant of lactating women
Patients with relevant co-morbidity such as clinically significant renal, hepatic or cardiac
impairment
Patients with disease severity different from that studied in clinical trials
Sub-populations with genetic polymorphisms
Patients of different ethnic origins
1.4.
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January 2012
Country
Country 1
Country 2 etc.
Country 1 etc.
Issue 2 etc.
1.5.
Action taken
Action 1
Action 2 etc.
Date
Date 1
Date 2 etc.
1.5.2. Details of important identified and potential risks (including newly identified)
For each important identified and potential risk provide the following if available:
Identified Risk <>
MedDRA PT terms
Seriousness/outcomes
Frequency with 95 % CI
Background incidence/prevalence
<describe use, dose, time and susceptibility data or other factors where available.
Cumulative hazard function may be provided>
Potential mechanisms
<describe>
Preventability
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Evidence source
<identify and cross refer to supporting data in CTD or annex data> or PM clinical trials,
safety studies, pharmacoepidemiological studies, PSUR, other safety reports etc.
1.6.
<>
<>
Possible mechanisms
<>
<>
Discussion
1.7.
1.7.1. For each indication, discuss the incidence, prevalence, mortality and demographic profile
of the target population
Indication/target population
<>
<>
<>
1.7.2. For each indication, discuss the important co-morbidity in the target population
List important co-morbidity in the target population.
Indication/target population
<>
<>
1.7.3. For each identified or potential risk e.g. hepatic failure, provide the epidemiology of the
164
January 2012
<>
Incidence of condition
<>
Prevalence of condition
<>
Mortality of condition
<>
1.8.
Identify risks which are believed to be common to the pharmacological class. If a risk which is
common to the pharmacological class is not thought to be a safety concern with the medicinal
product this should be justified and supporting evidence provided.
Risk
Frequency in
clinical trials
of medicinal
product
Risk 1
Comment
Product A
Product B
Product C
Review of adverse
reactions BMJ 2008: 5; 214-217
Risk 2 etc.
1.9.
165
January 2012
2.
PHARMACOVIGILANCE PLAN
The pharmacovigilance plan covers the actions intended to identify and characterize safety
concerns. It should not include actions intended to reduce or prevent risks.
2.1.
Briefly summarize the routine pharmacovigilance system. If the application is via CTD procedure
please cross refer to the section in Module 1.
2.2.
For each safety concern, provide a summary table of planned pharmacovigilance actions. Include
newly available results for updates to the pharmacovigilance plan. Where no action beyond routine
pharmacovigilance is planned, please justify.
2.3.
Safety concern
Planned action(s)
For each important identified or potential risk or missing information, provide the following:
Safety concern
<>
Action(s) proposed
<>
<>
<>
<>
<>
<>
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2.4.
2.5.
2.6.
Protocol version
Protocol status
Important missing
information
Present list of actions to be completed (ongoing and planned) with milestones and timelines.
Actions
Milestones/exposure
Milestones/calendar
time
167
Study status
January 2012
PART II
3.
The evaluation of the need for risk minimization activities should list all safety concerns presented
in section 1.10. Evaluate and justify whether routine (i.e. product information, labeling and
packaging) risk minimization activities will be sufficient or whether additional risk minimization
activities (e.g. educational material or training programmes for prescribers, pharmacists and
patients, restricted access programmes) will be required. If additional risk minimization activities
are necessary a risk minimization plan should be provided (see section 4). If, for any safety
concern, no risk minimization activities at all are proposed this should be fully justified.
3.1.
For each safety concern from section 1.10, provide a summary table of
planned actions
Safety concern
Yes/No
Yes/No
Yes/No
3.2.
168
January 2012
4.
For each important identified or potential risk for which additional risk minimization measures are
planned, provide the following:
Safety concern
Routine risk minimization
activities (i.e. product
information, labeling and
packaging)
Additional risk minimization
activity 1
(e.g. educational material or
training programmes for
prescribers, pharmacists and
patients, restricted access
programmes)
Proposed actions
Proposed actions
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January 2012
5.
Safety concern
Proposed pharmacovigilance
activities (routine and
additional)
Safety concern 1
E.g.
E.g.
routine pharmacovigilance
contraindication in section
4.3 of the SPC
Educational material
Controlled distribution
6.
Names
<>
Position
<>
Qualifications
<>
Signature
<>
170
January 2012
ANNEXES
List of annexes
Annex No
1
Description, Phase,
Countries
Design, No of patients
Follow-up
Estimated/Actual
completion date
Study ABC
Short description of
study (1 2 sentences
including comparator
name(s)/placebo) Phase
III Germany, USA,
Chile
Jan 2005
Study DEF
Etc
Feb 2008
Etc
Double-blind 1000 26
weeks
March 2005
Study JKL
Etc
Nov 2005
Etc
Feb 2005
Etc
Feb 2005
Paediatric studies
Study PQR
171
January 2012
Description
Study designs No of
patients Duration of
follow-up
Estimated/actual completion
date (dates when interim and
final study reports are
expected)
January 2012
1. Official statement
An official statement signed by the Local Safety Responsible to implement in Egypt the routine
pharmacovigilance activities and the activities stated in the submitted RMP as agreed with EPVC.
In addition, the implementation details described in the Global/EU RMP will be followed in Egypt
as well unless otherwise agreed with EPVC, and any updates to the Global/EU RMP will be
notified to EPVC immediately.
2. Summary of Risks
In reference to Global/EU RMP, this section should contain brief list of all the risks of the
medicinal product. Any additional risk which is Egypt/region-specific risk thus might not be
included in the Global/EU RMP should be described in this section as well. The risks should be
classified into 3 table lists as follow:
Type of the
activity
Safety
Concern
PV (routine, additional)
Risk minimization
(routine, additional)
Highlight
differences if any
(even minor
difference)
173
January 2012
Justification
a) If the MAH/Applicant proposes not to implement in Egypt any of the activities stated in the
Global/EU RMP; this should be clearly highlighted in the above table and comprehensive
justification should be supplied, in addition explanation of how the safety concern intended by
this activity will then be managed in Egypt.
b) If the MAH/Applicant proposes some differences (even minor ones) in the action plan of
specific activity to be followed in Egypt other than those described in the Global/EU RMP; the
differences should be clearly highlighted in the table and comprehensive justification should be
supplied as well.
c) If the MAH/Applicant will implement in Egypt additional activities over those stated in the
Global/EU RMP (e.g. due to Egypt-specific/region-specific safety concern/s or due to other
justified reason); this should be presented in details according to the following structure (see
Annex 5.1.1 section 2.3 Detailed action plan for specific safety concerns), as appropriate any
relevant documents should be annexed. It is also important to realize that for activities already
exist in the Global/EU RMP but different action plan in Egypt is proposed by MAH/Applicant
this action plan cannot be included in this section as if it is plan for additional activity, instead
the difference should be described in the previous table.
Safety concern
<>
Action(s) proposed
<>
<>
<>
<>
<>
<>
174
January 2012
Registration
Date(s) of
Marketing
Number(s)
Registration
Authorization
[Underline Harmonized)EU
Birth Date]
Holder
<>
<>
<>
<>
<>
<>
<>
<>
175
January 2012
Executive Summary
Introduction
World-Wide Market Authorization Status
Update of Regulatory Authority or MAH Actions Taken For Safety Reasons
Changes to Reference Safety Information
Patient Exposure
6.1. Exposure in clinical trials
6.2. Market Experience
7. Presentation of Individual Case Histories
7.1. Cases Presented as Line-Listings
7.2. Cases Presented as Summary Tabulations
7.3. MAHs Analysis of Individual Case Histories
8. Studies
8.1. Newly Analyzed Studies
8.2. Targeted New Safety Studies
8.3. Published Studies
8.4. Other Studies
9. Other information
9.1. Efficacy-related Information
9.2. Late-breaking Information
9.3. Risk Management Plan
9.4. Risk-Benefit Analysis Report
10. Overall Safety Evaluation
11. Conclusion
Appendices:
Appendix 1: Company Core Data Sheet/ Company Core Safety Information
Appendix 2: Summary of product characteristics (SPC)
Appendix 2a: local product information
Appendix 3: Relevant Post Authorization Safety Studies (PASS)
Appendix 4: Relevant Risk Management Plan (RMP)
Appended / included Tables:
Table 1: World-Wide Market Authorization Status
Table 2: Cases Presented In Line Listing
Table 3: Cases by Source, Seriousness and Listedness
Table 4: Medically Confirmed Cases by SOC
Table 5: Non-Medically Confirmed Cases by SOC
Table 6: Cumulative Summary - Serious and Unlisted Events
176
January 2012
1. Executive Summary
<Give a brief overview of the PSUR to provide the reader with a description of the most important
information. It should include a summary of all the following:
The worldwide marketing authorization status (including a list of countries where the product
is authorized/marketed and the authorized indications;
Other relevant regulatory information related to the period covered by the PSUR (e.g. any
urgent safety restriction should be highlighted);
Exposure data (National & International)
Number of new case reports received during the period covered by the PSUR and the
cumulative numbers;
Particular issues and safety concerns investigated;
Overall findings of the PSUR;
Conclusions.
<State here any review which might be performed by MAH for one or several specific safety concern(s), as
well as the nature of safety concerns that have been reviewed>.
2. Introduction
<briefly introduce the product so that the PSUR stands alone but is also placed in perspective relative to
previous PSURs and circumstances.>
<Reference should be made not only to product(s) covered by the PSUR but also those excluded.
Exclusions should be explained; for example, they may be covered in a separate PSUR (e.g. for a
combination product).>
Information about the medicinal product International Birth Date (IBD) or Harmonized Birth Date (HBD)
should be included here.>
January 2012
Describe the safety-related reasons that led to these and append documentation when appropriate; any
communication with Healthcare Professionals (e.g. Direct Healthcare Professional Communication
(DHPC), commonly called Dear Doctor Letter (DDL)) as a result of such action should also be described
with copies appended.>
<for each one of those actions, even if it was not taken; a clear statement indicating that should be
included>.
6. Patient Exposure
6.1. Exposure in clinical trials
When adverse reaction data from clinical studies are included in the PSUR, the relevant denominator(s)
should be provided.
178
January 2012
<A description of the criteria used to select cases for presentation should be provided.>
<Follow-up data on individual cases may be obtained subsequent to their inclusion in a PSUR. >
All serious adverse reactions and non-serious unlisted adverse reactions from spontaneous
reporting;
All serious adverse reactions (attributable to the medicinal product by either investigator or
sponsor) available from post-authorization safety studies (PASS) and other studies (including
those which are part of the Risk Management Plan) or named patient/compassionate use;
All serious adverse reactions, and non-serious unlisted adverse reactions from the literature;
All serious adverse reactions transmitted to the MAH by worldwide regulatory authorities.>
<In addition, the types of cases referenced below should be included as line-listings in the form of an annex
to the PSUR:
<Suspected transmission via a medicinal product of any infectious agent should be considered as a serious
adverse reaction
The following headings should usually be included in the line-listings (see appended Table 2)>
8. Studies
<All studies (non-clinical, clinical and epidemiological) yielding safety information (this includes lack of
efficacy data).>
179
January 2012
9. Other information
9.1. Efficacy-related Information
<For products used in prevention (e.g. vaccines) or in treatment of serious or life-threatening diseases (e.g.
antibiotics and antiviral products) or products used in healthy Consumers (e.g. contraceptives), medically
relevant lack of efficacy reports, which may represent a significant hazard, should be described and
explained.>
<Where appropriate, all other medically relevant reports of lack of efficacy should be discussed in this
section>.
180
January 2012
<When a specific Risk Management Plan is in place, it should be discussed. In this case, the status of the
Risk Management Plan and its amendments prior to the data lock point should be presented together with
all available study results.>
<The assessment of the effectiveness of the risk management system should be presented.>
< explicitly address any new safety concern on the following (lack of significant new information should
be mentioned for each):
Interactions;
Experience with overdose, deliberate or accidental, and its treatment;
Abuse or misuse;
Positive or negative experiences during pregnancy or lactation;
Experience in special patient groups (e.g. children. elderly, organ impaired, a qualitative
description of off-label use should be given);
Effects of long-term treatment;
Patient/Consumer and other non-healthcare professional reports if appropriate;
Prescription errors/medication errors, including those associated with invented names or with
the presentation of the medicinal products, that have safety implications, if available.>
11. Conclusion
< address the overall risk-benefit balance in the context of the data presented in the PSUR and:
indicate which safety data are not in accordance with previous cumulative experience and the
reference safety information (CCSI);
specify and justify any action recommended or initiated.
181
January 2012
<address the need to amend the SPC in the cover letter from the MAH, where consistency between the
CCSI and the SPC is cross-checked and any comment or planned action is proposed.
Having made a decision to amend the SPC, the MAH should submit a variation application at the same time
as the PSUR or, where this is not possible, state a proposed timetable for submission.>
182
January 2012
ANNEXES
List of annexes
Annex No
1
2a
Appended / included
Tables
1
183
January 2012
Approval
date
Local
product
trade
name
Dosage Indication
form
Registration
status
OR
Country
Sweden
Brazil
United Kingdom
Action-Date
A - 7/90
AR - 10/95
Launch Date
A - 10/91
A 1/93
2/92
3/93
AQ - 3/92
A - 4/94
6/92
12/90
Comments
Bactoff-IV
Bacgone
IV dosage form
Elderly (> 65) excluded
Bacgone-C
(PK)
(skin infs)
7/94
Japan
France
LA 12/92
V 9/92
Nigeria
A 5/93
A 9/93
7/93
Bactoff
Topical cream
To be refilled
Unrelated to safety
-
1/94
Bactoff
New indication
Etc.
184
January 2012
Comments
Country
Source
Age/
Daily Dose
Form /
Sex
[Dose
Frequency]
Route
Date of
onset of
reaction
Dates of
or
Treatment
Time to
Onset
Duration
Treatment or
mg/day
Patient
Outcome
[Preferred
Term]
185
Reaction
description
Event Verbatim
January 2012
Comment
Trials
Consumer
TOTAL
Serious Unlisted
Serious Listed
Subtotal
Non-serious
Unlisted
Non-serious Listed
Subtotal
TOTAL
Serious Serious
Preferred Term (PT)
Subtotal
Unlisted Listed
Skin and
subcutaneous
Pruritus
tissue
disorders
Skin
hyperpigmentation
etc.
Subtotal
Metabolism
and nutrition
disorders
Hypoglycaemia
etc.
Subtotal
TOTAL
186
January 2012
Preferred Term
(PT)
Serious Serious
Subtotal
Unlisted Listed
Hypertension
etc.
Subtotal
Dysgeusia
etc.
Subtotal
TOTAL
Previous
period
Current Cumulative
period
total
Pruritus
Skin hyperpigmentation
tissue
disorders
etc.
Subtotal
Metabolism
and nutrition
disorders
Hypoglycaemia
etc.
Subtotal
TOTAL
187
January 2012
Summary
<A brief description of the safety concern, recommendations for risk minimization
(e.g. contraindications, warnings, precautions of use) and, if applicable, switch to
alternative treatment, preferably in bullet points>
<Recall information, if applicable (e.g. pharmacy or patient level, date of recall)>
<A statement indicating that the information has been endorsed by CAPA/ EPVC
and the MAH, if applicable>
Style guide: The Summary section should be in larger font size than the other
sections of the DHPC.
Further information on the safety concern
<Important details about the safety concern (adverse reaction, seriousness, statement on the suspected
causal relationship, e.g. the pharmacodynamic mechanism, temporal relationship, positive re-challenge or
de-challenge, risk factors), also indicating the reason for disseminating the DHPC at this point in time>
<Placing of the risk in the context of the benefit>
<Revised Product Information text or, preferably, reference to revised Product Information in Annex>
<An estimation of the frequency of the adverse reaction or reporting rates with estimated patient exposure>
<A statement indicating any association between the adverse reaction and off-label use, if applicable>
<A statement indicating the context in which the assessment has been conducted >
<A schedule for follow-up action(s) by the MAH/EPVC, if applicable>
Further information on recommendations to healthcare professionals
<If needed, details on the recommendations for risk minimization >
<If needed, additional detailed instructions on how to use the new safety or therapeutic effectiveness
information>
Call for reporting
<A reminder of the need to report adverse reactions in accordance with the Egyptian Pharmacovigilance
spontaneous reporting system>
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January 2012
<Details (name, postal address, fax number, website address) on how to access the Egyptian
Pharmacovigilance spontaneous reporting system>
The Egyptian Pharmacovigilance Center (EPVC),
Address: 21 Abd Elaziz Al seoud-Manial-Cairo, PObox:11451
Tel: 0225354133/0225354130
Fax: 0223684194
E-mail: pv.center@eda.mohealth.gov.eg
Website: www.epvc.gov.eg
Details on how to report to the MAH>
Communication information
<Date and key messages of communication to the public>
<Content and dissemination mechanism of information to the general public or Patients, if applicable>
<Contact point details for access to further information, including relevant website address(es), telephone
numbers and a postal address>
Annexes:
<Text of the revised Product Information (with changes made visible), if applicable>
<Detailed scientific information, if necessary>
<List of literature references, if applicable>
189
January 2012
ANNEX (6)
6.2. Class 2:
Defects could cause illness or mistreatment, but are not Class 1.
Examples:
6.2.1: Mislabeling, e.g. wrong or missing text or figures
6.2.2: Missing or incorrect information (leaflets or inserts)
6.2.3: Microbial contamination of non-injectable, non-ophthalmic sterile product with medical
consequences
6.2.4: Chemical/physical contamination (significant impurities, cross-contamination, particulates)
6.2.5: Mix up of products in containers (rogues)
6.2.6: Non-compliance with specification (e.g. assay, stability, fill/weight)
6.2.7: Insecure closure with serious medical consequences (e.g. cytotoxics, child- resistant containers,
potent products).
6.3. Class 3:
Defects may not pose a significant hazard to health, but withdrawal may have been initiated for other
reasons.
Examples:
6.3.1: Faulty packaging, e.g. wrong or missing batch number or expiry date
6.3.2: Faulty closure
6.3.3: Contamination, e.g. microbial spoilage, dirt or detritus, particulate matter
190
January 2012
References
1- VOLUME 9A of The Rules Governing Medicinal Products in the European Union (Guidelines
on Pharmacovigilance for Medicinal Products for Human Use ), September 2008, EMEA.
2- Good Pharmacovigilance Practice Guide, Medicines and Healthcare products Regulatory
Agency, 2009
3- Saudi-Pharmacovigilance Guideline of Registered Medicines, November 2009, SFDA.
4- Guidelines for Good Pharmacoepidemiology Practices (GPP) International Society for
Pharmacoepidemiology. Guidelines for good pharmacoepidemiology practices (GPP).
Pharmacoepidemiol Drug Saf. 2005; 14 (8): 589-595. Available on the ISPE website
http://www.pharmacoepi.org/resources/guidelines_08027.cfm.
5- Note for Guidance on Minimizing the Risk of Transmitting Animal Spongiform
Encephalopathy Agents Via Human and Veterinary Products. Doc.Ref. EMEA/410/01 latest
version, available on EMEA website http://www.emea.europa.eu.
6- Council for International Organizations of Medical Sciences (CIOMS). Development and
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